Hypermethylated

Silencing can be done via DNA methylation

 Chemical Modification of Histones
• Histone proteins can be chemically modified by
acetylation,
• methylation, phosphorylation, or addition of ubiquitin
(sometimes called epigenetic marks or epigenetic tags).

• An increased acetylation of histone proteins will make a

DNA segment more likely to be transcribed into RNA and
hence any genes in that DNA segment will be expressed
(i.e., ↑ acetylation of histones = ↑ expression of
genes).
– Usually (as far as the USMLE is concerned):
↑methylation of histones = ↓ expression of genes
• The mechanism that determines the location and
combination of epigenetic tags is unknown.
• This is another part of the epigenetic code that must be
deciphered.
Histone Modifications

Histones determine how

accessible the genome is for
transcription. Different
modifications can make
genes more or less able to
be transcribed

Barr bodies are nearly

completely silenced by
histones!
(heterochromatin)
 ncRNAs – especially miRNAs
Can include lncRNA, siRNA,
miRNA, piRNA, snoRNA, and
tRNAs – considered epigenetic
because they regulate post-
transcriptional modification,
gene expression, preservation
or destruction of mRNA
transcripts

Regarding miRNAs – they can

either repress translation or
actually cleave mRNA

21-25nt in length (very tiny

sequences)

Smith-Vikos and Slack, 2012

miRNAs silence genes!!!
Journal of Cell Science
How does this affect phenotype?
• Epigenetic changes can switch genes on or off
and determine which genes are transcribed.
• Epigenetic silencing is one way to turn genes off,
and it can contribute to differential expression.
However it can also turn on (increase expression)
genes that shouldn’t be expressed…
• Epigenetic changes might also explain, in
part, why genetic twins are not phenotypically
identical.
• In addition, epigenetics is important for X-
chromosome inactivation in female mammals,
- which is necessary so that females do not have
twice the number of X-chromosome gene
products as males.
No methylation: Methylation:
Gene “ON” Gene “OFF”
DNA methylation levels: The
Epigenetic Clock
Although identical
twins share the
same genes, their
phenotypes diverge
the older they get
(“epigenetic drift”).
 X Chromosome inactivation
(Lyonization*)
• The X chromosome contains over 1,000
genes that are essential for proper
development and cell viability.
• Most females carry two copies of the X
chromosome while most males only have
one.
• To correct this imbalance, mammalian
females have evolved a unique mechanism
X-chromosome inactivation (XCI), female
mammals transcriptionally silence one of
their two Xs in a complex and highly
coordinated manner.
*XCI can also be called Lyonization in some texts. This is named after Mary Lyon, an incredible pioneer in her field who
discovered this phenomenon in 1961
 Mode of action of XIST
• The epigenetic process of XCI is achieved
by differential methylation (a form of
imprinting) and is initiated by a gene, XIST
('X inactivation specific transcript'), which
maps within the X-inactivation centre at
Xq13.3.
• XIST is expressed only from the inactive X
chromosome produces RNA that spreads an
inactivation methylation signal up and
down the X chromosome on which it is
located.
• Not all of the X chromosome is inactivated.

XIST RNA paints the X-chromosome

territory in interphase human female cells
 Fabry’s disease
• This 46 year-old male was referred for
dermatologic evaluation of a purpura on his
abdomen. He was being treated for
proteinuria and cardiac symptoms. The
diagnosis of angiokeratoma corporis
diffusa (Fabry disease) was made clinically
and confirmed by demonstration of the
deficient leukocyte alpha-Gal A activity.
• The patient subsequently developed
cerebrovascular symptoms, coronary disease,
and renal failure, and died from a recurrent
myocardial infarction.
• Fabry's disease is an X-linked lysosomal
storage disorder caused by a deficiency of
alpha-galactosidase A enzyme with the
progressive accumulation of
globotriaosylceramide in vascular
endothelial cells leading to cardiovascular,
renal, gastrointestinal, neuropathic, lenticular,
and dermatological manifestations.
Lancet, 2011
 Women With Fabry Disease
• Fabry Disease is an inherited disorder that was once thought to
affect only males.
• Females were called ‘carriers’ because it was believed that they
carried the gene for the disorder without developing symptoms.
•Each organ in a female’s body has its own X-
inactivation pattern.
•Sometimes, an X-inactivation pattern is not
random and the distribution of cells active vs.
non-active is not evenly distributed throughout
their body.
•For unknown reasons*, there may be more cells
with the ‘Fabry X’ turned on, and fewer cells with
the healthy, or ‘non-Fabry X’ turned on.
•When this is the case, any tissues containing these
cells will have an uneven distribution of enzyme. Normal (left), Mosaic (right)
•In other words, rather than 50/50, she may have
70% of her cells with no enzyme, and only 30% with
enzyme.
*not quite so unknown anymore…
Di Risi, T., Vinciguerra, R., Cuomo, M. et al. DNA methylation impact on Fabry disease. Clin
Epigenet 13, 24 (2021). https://doi.org/10.1186/s13148-021-01019-3
 Genomic Imprinting
• It is now recognized that different clinical features can result
depending on whether a gene is inherited from the father or
from the mother.
• This 'parent of origin' effect is referred to as genomic
imprinting, and methylation of DNA is thought to be the main
mechanism by which expression is modified.
• Methylation is the imprint applied to certain DNA sequences in
their passage through gametogenesis,
• only a small proportion of the human genome is in fact subjected to
this process.
• The differential allele expression (i .e. maternal or paternal)
may occur in all somatic cells, or in specific tissues or stages of
development.
• Thus far, more than 90 human genes are known to be imprinted
and the regions involved are known as differentially methylated
regions (DMRs).
• These DMRs include imprinting control regions (ICRs) that control
gene expression across imprinted domains.
 Uniparental Disomy
• A unique feature to imprinted conditions is the unusual situation in
which a child inherits both copies of a chromosome from one
parent and none from the other. This is known as uniparental
disomy (UPD).
• Uniparental disomy usually arises due to an error in meiosis.
• Two chromosomes in either the egg or sperm cell fail to separate
and both get passed to the fetus. As a result, the fetus inherits three
chromosomes (trisomy) rather than two.
• In relatively rare situations, one of the three chromosomes is lost
(termed trisomy rescue*), resulting in a 'normal' two-chromosome
state (disomic) after fertilization. One-third of the time, this loss will
result in uniparental disomy.

* We talked about
trisomy rescue in
mosaicism too
 UPD vs deletion patterns:
Angelman Syndrome Prader-Willi Syndrome
• Caused by maternal • Caused by paternal
deletion on 15q deletion on 15q
• But also caused by paternal • But also caused by
uniparental disomy (no maternal uniparental
maternal copies of genes disomy (no paternal copies
available) of genes available)
Which UPD is likely more rare??
Maternal Paternal Paternal Maternal
Normal:
deletion: UPD: deletion: UPD:
♀ ♂ ♂ ♂ ♀ ♂ ♀ ♂ ♀ ♀
 Beckwith-Wiedemann
Syndrome
Another example of an imprinting disorder

Like AS/PWS, however this time the deletion

or modification is seen in the region of
11p15.5 (short arm of chromosome 11)

This is an imprinted region where the

maternal copy of ch11 expresses the gene,
paternal copy is silenced. Abnormalities
cause an overgrowth of several organs -
can be asymmetric
*omphalocele
Both a maternal deletion or paternal
uniparental disomy can cause this disease

The opposite
1 in 13,700 births
phenomenon can cause
But 1 in 4000 ART
Russell-Silver Syndrome
(but don’t worry about it)
Some nice reviews if interested:
https://www.karger.com/Article/Fulltext/447413
https://www.mdpi.com/1422-0067/20/17/4219/htm (youtube My BWS Baby)
 Rett Syndrome
• With a prevalence of 1 in 8,500 girls, Rett syndrome is one of the
most frequent heritable causes of intellectual disability in
females.
• Supportive clinical findings include breathing disturbances,
impairment of sleeping pattern, and progressive scoliosis.
• Rett syndrome is an X-linked disorder caused by mutations
in the MECP2 gene on chromosome Xq28.
• The normal gene product, MeCP2 (methyl-CpG-binding protein
2), binds to methylated DNA in the human genome and
functions as a master regulator of gene transcription*.
• Thus, when MeCP2 function is lost, the transcription of
thousands of genes is altered.
*Note – yes, this still involves
splicing…
 The Barker Hypothesis- The Developmental
Origins of Health and Disease (DOHaD):
Low birth weight babies were assessed for disease later in
life and Barker et al found that there was an increased
susceptibility to CVD and metabolic syndrome

Tissues and organs in sensitive periods of development

show permanent functional changes due to the adverse
environment:
Metabolic syndrome (plus NAFLD)
Neuropsychiatric disease
CVD

Usually accompanied by
inflammatory and immune changes

Developmental Reprogramming- An
organism can respond to the surrounding
environment during cell differentiation, which
changes the phenotype and gene expression
without modifying the genetic code.
Critical Windows of Exposure in the Development of
Disease

Adapted from Tohyama, 2018

Current Topics in Environmental Health and Preventive Medicine

The earlier the exposure to an adverse environmental insult, the

more an individual can be affected

Dynamic changes in epigenetics regulate transcriptional activity of genes as cells

acquire specific functions (differentiate)

While many epigenetic changes can be reversed, a subset are permanent and can
affect cell metabolism, survival, proliferation, and activity

Environmental dysregulation can disrupt normal epigenetic programming, thus

causing disease later in life
 Dynamic mutations cont…
• Anticipation. Dynamic
mutations demonstrate
anticipation. Anticipation is
one of the hallmarks of
diseases caused by dynamic
mutations.

Anticipation means that a

genetic disorder displays an
earlier age of onset and/or
a greater degree of
severity in successive
generations of the family
pedigree.
 Dynamic mutations
Dynamic mutations are divided into two categories:
• Highly expanded repeats outside the gene
(introns/UTRs)
o Fragile X syndrome
o Friedreich Ataxia
o Myotonic dystrophy type 1

• Moderately expanded CAG repeats inside the gene

(exons)
o Huntington disease
o Spinal and Bulbar Muscular atrophy ( Kennedy syndrome)
o Spinocerebellar ataxia type 3(Machedo-Joseph disease)
Simple Repetitive Sequences
• Depending on the location of the unstable
sequence (e.g. coding sequence, intron, promoter
or intergenic region), its amplification may have
an effect on the expression of one or more
gene(s)
• Can cause;
1. production of an altered protein (if inside exon),

2. accumulation of expanded messenger

ribonucleic acid (mRNA) molecules (if in 3’ UTR) or

3. Downregulation of transcription (if in 5’ UTR)

4. Issues with splicing (if inside an intron)

 Sex-specific expansion
• It is noteworthy that the likelihood of repeat
expansion differs between spermatogenesis and
oogenesis.

• In the case of Huntington disease, repeat

expansion occurs mostly through spermatogenesis,
while a Fragile X premutation only develops into a
full mutation through oogenesis.

• In the case of myotonic dystrophy, this is more

complex. Small fragments with fewer than 100 repeats typically
expand when transmitted through spermatogenesis,
while expansion of large fragments may occur
through oogenesis.
 Important trinucleotide repeats
Normal Full
Repeat
Disease Inheritance Repeat Gene allele mutation
Location repeats
repeats

Huntington
Autosomal
Disease CAG HTT Exon ≤26 40+
Dominant
(chorea)
Spinocerebellar Differing
Autosomal Exon (can Differing*
ataxias CAG SCAX * (20s-
Dominant differ) (but low)
(various) 40s)

Fragile X X-linked 200 to

CGG FMR1 5’ UTR 5-40
syndrome Dominant 1000s

Myotonic Autosomal 50 to
CTG DMPK 3’ UTR 5-34
dystrophy Dominant 1000s

Friedreich Autosomal 66 to
GAA FXN Intron 5-33
ataxia Recessive 1000s

*There are 30+ spinocerebellar ataxias so we are generalizing what is most common
In SCA6, for example, the threshold for disease is as low as 20 repeats
 Fragile X Diagnosis
• Although certain physical and behavioral
features are often associated with fragile
X syndrome, they are not always
present.

• In at least 10% of cases in males,

intellectual impairment is the only
presenting sign.

• The classic triad of long face,

prominent ears and macroorchidism
is present in just 60% of cases.
Intellectual disability is not a constant,
either.

• Approximately 15% of males with fragile

X syndrome have an IQ above 70.

• Cytogenetic test: It is not very reliable

as, among the patients, only a 55% of
females and 80% of males have a
detectable fragile X site.
 Fragile X syndrome
• The most characteristic (non-physical) signs
reported are:

1. Intelligence problems, ranging from learning

disabilities to severe intellectual disabilities
2. Social and emotional problems, such as aggression in
boys or shyness in girls
3. Speech and language problems, especially in boys

• Despite being a dominant genetic disease, fragile X

syndrome is mostly encountered in males, as the
FMR1 gene is in the X chromosome.
• So, the syndrome affects mostly X*Y males and
carrier X*X females tend to manifest a milder
phenotype.
Huntington Disease (Huntington
Chorea
• Huntington chorea is the first disease whereby genetic analysis
was used for asymptomatic individuals who were at risk in order
to predict their neurological fate.
• It continues to be one of the most prominent examples of
predictive testing in the absence of curative therapeutic
options.
• The incidence in Western Europe is approximately 1 in 20,000
individuals.
• It appears less frequent in Japanese, Chinese, Finnish, and
African ethnicities
• Men and women are equally affected.
• Carriers for Huntington disease are almost always asymptomatic
in childhood and adolescence.
• The age of onset for the disease is typically between 30 and 50
years, with a peak around 45 years.
• Only in 5% to 10% of the cases does the disease manifest before
age 20 years.
• The classic triad of symptoms for Huntington diseases includes:
■ Movement disturbances (especially extrapyramidal motor symptoms)
■ Cognitive disturbances (including dementia)
■ Psychiatric abnormalities
• There is significant danger of suicide, especially during the early
stages of the disease, due to depression.
In persons with HD, the structures of
the basal ganglia are a lot smaller than
normal
This reduction happens because nerve
cells of the striatum are the first to die as
HD progresses.
Although other parts of the brain are also
affected during HD, the basal
ganglia appear to be the most heavily
damaged.
 Genetics and Etiology
• Huntington disease is one of the very few autosomal dominant
heritable diseases for which the manifestation of the disease does not
significantly differ for homozygous and heterozygous carriers
(complete phenotypic dominance).
• The time of onset of the disease is the same; the only difference is that
homozygous patients progress somewhat faster.
• New mutations are extremely rare
• The disease results from the expansion of a polyglutamine sequence
(CAG)n in the coding sequence of the HTT gene on chromosome 4p16.3,
which codes for the protein huntingtin.
• Individuals with 10 to 35 CAG repeats have no disease risk. In the case of
27 to 35 repeats, however, a repeat expansion can occur in the germ line,
so that children may be affected by the disease (premutation).
• Individuals with 36 to 39 repeats may or may not develop symptoms of
Huntington disease (incomplete penetrance).
• Beginning with 40 CAG repeats, all affected individuals will develop
Huntington disease (100% penetrance).
• There is an inverse correlation between the number of repeats and the age
of onset of the disease;
• the higher the number of repeats, the earlier the onset. It is impossible,
however, to predict the age of onset in individual cases
 Spinocerebellar Ataxias
• a group of inherited
neurological disorders that are
both clinically and genetically
heterogeneous.

• Most of these display

autosomal dominant
inheritance, but recessive and
X-linked types have also been
recognized.

• The autosomal dominant types

are numbered in the order of
which their genetic loci are
described—spinocerebellar
ataxia types 1 to 31 (SCA1 to
SCA31).
 Friedreich Ataxia
• Friedreich ataxia (hereditary spinal ataxia) is the most notable
autosomal recessive heritable ataxia.

• In contrast to most SCAs, the clinical onset of symptoms in

Friedreich ataxia is before the age of 25 years, usually between 10
and 15 years.

• With a prevalence of 1 in 25,000 to 1 in 50,000, it is the most

frequent heritable ataxia in Europe and the Middle East.

• In Friedreich’s ataxia the spinal cord and peripheral nerves

degenerate, becoming thinner. The cerebellum, part of the brain
that coordinates balance and movement, also degenerates to a
lesser extent.

• This damage results in awkward, unsteady movements and

impaired sensory functions.

• The disorder eventually causes problems in the heart and spine,

and some people with the condition develop diabetes.
– What might be happening here???
 Myotonic Dystrophy type 1
• Myotonic dystrophy (or dystrophia myotonica, DM) is the most common adult
muscular dystrophy in humans.
• Its an Autosomal Dominant disorder
• In myotonic dystrophy (DM) there is a CTG repeat in the 3' UTR of the DMPK
gene (myotonin protein kinase) which is expressed in many tissues.
• The "expanded" mRNA stays in the nucleus and forms nuclear aggregates.
• Therefore, there is an insufficient amount of the gene product.
• Myotonic dystrophy is characterized by progressive muscle wasting and
weakness.
• People with this disorder often have prolonged muscle contractions
(myotonia) and are not able to relax certain muscles after use.

• For example, a person may have difficulty releasing their grip on a

doorknob or handle. Also, affected people may have slurred speech or
temporary locking of their jaw.

Myotonic Dystropy Type 2:

❖ Abnormal CNBP gene •
❖ Rare type •
❖ Usually less severe than type I •
❖ CCTG (tetranucleotide) repeat (not a trinucleotide disorder)
• The expansion occurs more in oogenesis.

• The myotonin phosphokinase (PK) is a signal transduction pathway protein

and when it is not produced in sufficient quantities, the entire pathway is
down regulated magnifying the effect of the mutation and resulting in an AD
phenotype with early onset of the disorder.

DMPK gene
dystrophia myotonica protein kinase
 Common Traits of Multifactorial
Diseases
1. The disease can occur in isolation, with affected children born to
unaffected parents.
• Although familial aggregation is also common (i.e., there may be
multiple cases in the same family), there is no clear Mendelian
pattern of inheritance.
2. Environmental influences can increase or decrease the risk of
the disease.
3. The disease occurs more frequently in one gender than in the
other, but it is not a sex-limited trait.

• In addition, first-degree relatives of individuals belonging to

the more rarely affected gender have a higher risk of bearing
the disease.
• The concordance rates in monozygotic and dizygotic twins
contradict Mendelian proportions.
• A concordance rate is a measure of the rate at which both twins
bear a specific disease.
4. The disease occurs more frequently in a specific ethnic group
 Multifactorial Inheritance:
Continuous (quantitative) characteristics

• Inheritance controlled by many

genes with small additive
effects (polygenic) plus the
effects of the environment

• Large number of genetic

factors, each making only a
small contribution to the final
phenotype

• Clinical clue: One organ system

affected – usually with genetic
diseases, multiple organs are
affected!
Family studies of the incidence of cleft
lip (± cleft palate)
Anomaly Risk to sibs %

Bilateral cleft lip and palate 5.7

Unilateral cleft lip and palate 4.2

Unilateral cleft lip alone 2.5

The more severe the manifestation of a multifactorial condition, the

greater the probability of recurrence
 Some multifactorial conditions have an
unequal sex ratio
Condition Sex ratio
(males to females)

Pyloric stenosis 5 to 1
Hirschprung disease 3 to 1
Congenital dislocation of hip 1 to 6
Talipes (club foot) 2 to 1
Rheumatoid arthritis 1 to 3
Peptic ulcer 2 to 1

For some conditions there must be a different threshold for males

and females
 Pyloric Stenosis

5x more
common in
boys than girls

• Recurrence risk is greater if proband is of less commonly affected sex

• Eg Congenital pyloric stenosis
– Male probands
• Recurrence in brothers 3.8%
• Recurrence in sisters 2.7%
– Female proband
• Recurrence in brothers 9.2%
• Recurrence in sisters 3.8%
 Multifactorial inheritance:
Factors increasing probability of recurrence
in a particular family
*
• Close relationship to proband

• High heritability of disorder

• Proband of more rarely affected sex

• Severe or early onset disease

• Multiple family members affected

All these suggest that the family has a higher risk of the disorder –
genes of higher effect or more adverse environmental influences
*a person serving as the starting point for the genetic study of a family
(used especially in medicine and psychiatry).
 Multifactorial Inheritance
The Liability/Threshold Model
• One theory, a disease develops
and is expressed only after a
certain critical liability
threshold is reached.
• The further the liability
threshold is surpassed, the
more severe the disease
phenotype is.
• In contrast, an individual who
does not reach the liability
threshold will never develop the
disease.
• Therefore, an individual either
has the disease or does not, and
• the disease shows discontinuous
variation
 Multifactorial Inheritance
The Liability/Threshold Model
• The risk of recurrence for first-degree
relatives (i.e. siblings and offspring)
approximates to the square root of
the general population incidence.

• Thus, if the incidence is 1 in 1000, the

sibling and off spring risk will equal
approximately 1 in 32, or 3%
 Heritability
• Heritability (H) is the estimate of the contribution that the
genetic component makes to a trait and ranges from 0 →1.

• If H = 0, then the variation in a trait among individuals in a

population is entirely due to the environmental component.

• If H = 1, then the variation in a trait among individuals in a

population is entirely due to the genetic component.

• The heritability increases (i.e., H tends toward 1) as the

concordance(two individuals having the same trait) increases in
monozygotic (MZ) twins versus dizygotic (DZ) twins
• (↑heritability= ↑concordance).

• This is indicated in the following examples:

o Idiopathic seizures ( high heritability)
o Cleft palate ( low heritability)
 Shared Genes – Degree of
Relatives
• Terminology used for relatives of the proband depends on the
number of shared genes.
• First-degree: parents, sibs and offspring of the proband share 50%
(1/2) of their genes.
• Second-degree: grandparents and grandchildren, uncles and aunts,
nephews and nieces, half-sibs share 25% (1/4) of their genes.
• Third-degree: first cousins, great-grandparents, great
grandchildren share 12.5% (1/8) of their genes.

(I’ll draw the concept out above)

 Summary of the characteristics
of multifactorial inheritance
1. Although the disorder is obviously familial, there is no distinctive
pattern of inheritance within a single family.
2. The risk to first-degree relatives, determined from family studies, is
approximately the square root of the population risk.
3. The risk is sharply lower for second-degree than for first-degree
relatives, but it declines less rapidly for more remote relatives.
4. The recurrence risk is higher when more than one family member is
affected.
5. The more severe the malformation, the greater the recurrence risk.
6. If a multifactorial trait is more frequent in one sex than in the other, the
risk is higher for relatives of patients of the less susceptible sex.
7. If the concordance rate in DZ twins is less than half the rate in MZ twins,
the trait cannot be autosomal dominant, and if it is less than a quarter of
the MZ rate, it cannot be autosomal recessive.
8. An increased recurrence risk when the parents are consanguineous
suggests that multiple factors with additive effects may be involved.
 Genetic Polymorphism
• Polymorphism is the occurrence in a population of
two or more genetically determined forms (alleles,
sequence variants) in such frequencies that the rarest of
them could not be maintained by mutation alone.

• Linkage analysis requires a large number of highly

polymorphic markers to be tracked throughout the
genome.

• Over FOUR MILLION polymorphisms have been

identified at specific loci in one person
– These occur on average once every 1000 bases
 Types of
polymorphisms
Short tandem repeat
polymorphisms (STRPs aka
microsatellites) –
Short repeats of 2-6 base
long sequences. Often have
many types of alleles in the
population, each allele
having a different number of
repeats

Single nucleotide polymorphisms (SNPs) – individual nucleotide positions

where a point mutation occurred that is heritable. SNPs are usually two-allele
markers like what is seen in the diagram. At this specific point, you either
have a G or a C with G being allele 1 and C being allele 2
 Genetic Linkage
• Linkage is the quantification of how close two or more
loci are on a chromosome that sort together during
meiosis crossover
– Linkage between genes occurs because crossover very rarely
occurs between loci that are close together!!
• Recall: crossover is the exchange of DNA between
homologous chromosomes in meiosis I
 Genetic Linkage
• Mendel's third law - the principle
of independent assortment - states
that “members of different gene
pairs assort to gametes
independently of one another”

• But if two loci are positioned

close together on the same
chromosome, so that alleles at
these loci are inherited together
more often than not, these loci
are said to be linked.

• In effect, the two loci are

sufficiently close together for it to
be unlikely* that they will be
separated by a cross-over, or
recombination, during meiosis I.
*it still happens but very rarely (see recombinant
vs parental probabilities in figure)
 Recombination Fraction
• The recombination fraction, which is usually designated as θ
(Greek theta), is a measure of the distance separating two
loci,
• or more precisely an indication of the likelihood that a cross-over will
occur between them.

• If two loci are not linked then θ equals 0.5 as, on average, genes at
unlinked loci will segregate together during 50% of all meioses.
• If θ equals 0.05, this means that on average the alleles will
segregate together 19 times out of 20,
• i.e. a cross-over will occur between them during, on average, only
1 in 20 meioses.
 Centimorgans
• The unit of measurement for genetic linkage is known as
a map unit or centimorgan (cM).
• If two loci are 1 cM apart, a cross-over occurs between
them during, on average, only 1 in every 100
meioses, i.e. θ = 0.01 .
• Centimorgans are a measure of the genetic or linkage
distance between two loci.
• This is not the same as physical distance, which is
measured in base pairs but often 1cM is about 1
million base pairs.
• However, the relationship between linkage map units and
physical length is not linear.
• Some chromosome regions appear to be particularly
prone to recombination, so-called ‘hot spots’.
• Recombination is much less frequent near centromeres
and telomeres
 Linkage Analysis
• Involves study of the disease in large families
with polymorphic markers from each
chromosome.

• Eventually a marker will be identified that co-

segregates with the disease more often than
would be expected by chance,
• i.e. the marker and disease loci are linked.

• To study linkage the use of likelihood ratios

within an entire population, the logarithms of
which are known as LOD scores (logarithm of
the odds) are used.
• When interpreting LOD scores, we use the following
rules:

– If LOD score >3.0, there is statistical evidence of linkage

– If LOD score <-2.0, there is statistical evidence of non-
linkage
– Anything between -2 and 3 is non-significant aka can’t be
determined one way or the other

• In this table, we see only one case of significant

linkage with a recombinant frequency of 0.1 – i.e. the
most likely distance between the gene is a
recombination frequency of 10% or 10cM
 GWAS
• A genome-wide association study is an
examination of many common genetic
variants in different individuals to see if any
variant is associated with a trait.
• GWAS typically focus on associations
between single-nucleotide
polymorphisms (SNPs) and traits like major
diseases.
• These studies normally compare the DNA of
two groups of participants: people with the
disease (cases) and similar people without
(controls).
 Human Leukocyte Antigen
(HLA)
• The human leukocyte antigen (HLA) system
is the name of the loci of genes that encode
for major histocompatibility complex (MHC)
in humans.
• The super-locus contains a large number of
genes related to immune system function in
humans.
• This group of genes resides on chromosome 6
and encodes cell-surface antigen-presenting
proteins and has many other functions.
• The HLA genes are the human versions of the
MHC genes that are found in most vertebrates
(and thus are the most studied of the MHC
genes).
• The major HLAs are essential elements for
immune function.
Common HLA associated disorders
 Human Leukocyte Antigen
(HLA)
• They are also important in disease defense. They are the major
cause of organ transplant rejections.
• They may protect against or fail to protect (if down-regulated by
an infection) against cancers.
• Mutations in HLA may be linked to autoimmune
disease (examples: type I diabetes, Crohn’s disease).

• Aside from the genes encoding the 6 major antigen-presenting

proteins, there are a large number of other genes, many involved in
immune function, located on the HLA complex.
• Diversity of HLAs in the human population is one aspect of
disease defense, and, as a result, the chance of two unrelated
individuals with identical HLA molecules on all loci is very low.
• HLA genes have historically been identified as a result of the ability to
successfully transplant organs between HLA-similar individuals.
 Haplotype
• These are genes that are often inherited together.
Effectively, they are very strongly linked. The HLA
complex genes have several genes that are inherited
together in a pattern that increase the susceptibility
to multiple diseases
 Type 1 Diabetes
• Type 1 diabetes (T1D) is caused by destruction of
insulin-secreting β-cells in the islets of
Langerhans of the pancreas via autoimmune
insulitis.
• This results in an absolute insulin deficiency.
• Although T1D is rarely familial, genetic factors do
play an important, predisposing role.
• Like many autoimmune disorders, T1D is strongly
associated with certain variants of highly
polymorphic human leukocyte antigen (HLA) genes.
• Since variants in adjacent HLA genes often show
strong linkage disequilibrium, association studies
are carried out with regard to specific haplotypes
(combinations of variants).
 Type 1 Diabetes
• The HLA class II genes DRB1, DQA1, and DQB1 are of
particular importance for the development of T1D;
• more than 90% of patients carry the DR3 or DR4
haplotypes on at least one allele, whereas fewer than
40% of normal controls have these haplotypes.
• Individuals heterozygous for both DR3 and DR4 have
a risk of approximately 1 in 15 of developing type 1
diabetes versus a risk of 1 in 300 in the general
population.
• In contrast, there is also a protective DR2 haplotype
that is found in 20% of the general Caucasian
population but less than 1% of Caucasian T1D patients.
• The HLA alleles are in close proximity to several
immune-regulatory genes on chromosome 6.
 Celiac Genetics
• Coeliac disease is a common disorder. Its prevalence has been
estimated at about 1 in 100 people worldwide.
• The risk of developing celiac disease is increased by certain
variants of the HLA-DQA1 and HLA-DQB1 genes.
• These genes provide instructions for making proteins that play a
critical role in the immune system.
• The proteins produced from the HLA-DQA1 and HLA-DQB1 genes
attach (bind) to each other to form a functional protein complex
called an antigen-binding DQαβ heterodimer.
• This complex, which is present on the surface of certain immune
system cells, attaches to protein fragments (peptides) outside the
cell.
• If the immune system recognizes the peptides as foreign
(such as viral or bacterial peptides), it triggers a response to
attack the invading viruses or bacteria.
• Coeliac disease is associated with an inappropriate immune
response to a segment of the gluten protein called gliadin.
• This inappropriate activation of the immune system causes
inflammation that damages the body's organs and tissues and
leads to the signs and symptoms of celiac disease.
 HLA-B27 – the link between
inflammatory arthritis and the gut
• MHC-I class surface antigen that is strongly
associated with ankylosing spondylitis and other
forms of inflammatory or autoimmune diseases
– Other forms include psoriatic arthritis, inflammatory bowel
diseases (Crohn’s and UC), and reactive arthritis
– 90% of Caucasians with ankylosing spondylitis are positive
for HLA-B27 and therefore this is a common diagnostic
criteria for the disease
 Human birth defects - Malformation

• A morphological defect
caused by an
intrinsically abnormal
developmental
process.

• E,g., polydactyly, oligodactyly,

spina bifida, cleft palate
▪ beginning (fertilization) ,
▪ during embryogenesis ( 3
to 8 weeks ),
▪ organogenesis and
▪ Nutritional ( folate
deficiency)

*can be environmental re: neural tube defects - folate

Intrinsic: abnormalities present from the beginning or very early stages
 Human birth defects - Dysplasia

• A morphological
defect caused by an
abnormal
organization of
cells into tissues.
▪ embryonic period
(weeks 3 to 8 of
gestation)
▪ organogenesis.
• E.g., some forms of
dwarfism and congenital
ectodermal dysplasia.

• Often genetic (but can be

environmental)
 Human birth defects - Disruptions

• Not genetic based. A

morphological defect
caused by the breakdown
of or interference with an
intrinsically normal
developmental process. A
disruption occurs at any
time during gestation.

• E.g., bowel atresia due to

vascular accidents, amniotic
band disruptions, and most
cases of porencephaly (cystic
lesions of the brain).

Bowel atresia – normal formation not able to happen as blood flow is disrupted
 Human birth defects - Deformation

• Not genetic based. An

abnormality of form or
position of a body part
caused by mechanical
forces that interfere with
normal growth or position
of the fetus in utero. A
deformation occurs usually in
the second and third
trimester of the pregnancy.
• E.g., abnormal position of the
feet, clubfoot, and abnormal
moulding of the head

Congenital dislocation of the knee

associated with abnormal fetal position
 VACTERL Association (VATERR
Association)
• The name VACTERL is an acronym
formed by the first letters of the
possible individual symptoms.
• VACTERL occurs as a sporadic
combination of several abnormalities,
with a frequency of 1 out of 10,000
newborns.
• Boys are affected twice as often as girls,
with a male-to-female ratio of 2.2:1.
 V - Vertebral anomalies 70%
A - Anal atresia 80%
C - Cardiovascular anomalies 55%
T - Tracheoesophageal fistula 70%
E - Esophageal atresia 70%
R - Renal (Kidney) and/or radial anomalies 55%
L - Limb defects 65%

• The prognosis depends mostly on the severity of the

various malformations.
• Between 5% and 25% of infants born with VACTERL
association die within their first year.
• The prognosis is excellent if all existing malformations
can be successfully corrected.
• These children generally have normal cognitive
development.

*can be associated with diabetic mothers – environmental cause!

 Determination of left and right axis
• L/R axis determination begins with
the asymmetric (future left-side)
expression of the signaling protein
Sonic hedgehog (Shh) protein
from the notochord, which is
located in the midline.

• After the L/R axis is determined in

the embryo, the L/R asymmetry of a
number of anatomical organs (e.g.,
heart, liver, stomach) can then be
patterned Situs inversus, the complete reversion
or mirroring of organs is thought to be
• Clinical consideration: Primary caused by a defect in this body
Ciliary Dyskinesia (PCD; or planning!
Immotile Cilia
Syndrome)/Kartagener
Syndrome.
 Primary ciliary dyskinesia
• PCD is an autosomal recessive genetic disorder
caused by missense, nonsense, splice site,insertion,
and deletion mutations where at least two different
genes have been implicated thus far: DNAH5 gene and
DNAI1 gene
2. These mutations result in cilia that are
immotile (ciliary immotility), beat
abnormally (ciliary dyskinesia), or are
absent (ciliary aplasia).
3. PCD affected individuals inherit the
mutant genes from the parents who are
obligate asymptomatic heterozygotes.
4. Prevalence. The prevalence of PCD is
1/12,000 to 17,000 births in the US
population.
Clinical features: Sinusitis, Pulmonary
infections, Clubbing, Sterility. and situs
inversus. PCD with situs invertalis is
Karteneger’s syndrome.
 Determination of anterior/ posterior axis
(top to bottom in our spine in humans)
• A large number of gene regulatory
proteins called homeodomain
proteins play a role in determining
the normal A/P location of a
number of anatomical structures.

• All homeotic genes encode for

homeodomain proteins, which are
gene regulatory proteins. A
homeotic mutation is one in which
one body part is substituted for
another. Homeotic mutations were
first studied in Drosophila (e.g., legs
sprout from the head in place of
antennae).
 Disorders related to Fibroblast growth
factor
• Achondroplasia (AC).
Skeletal dysplasias are
conditions of abnormal bone
growth and are typically
called dwarfisms. There are
short-limb dysplasias (short
limbs relative to the length of
the trunk) and short-trunk
dysplasias (short trunk
relative to the length of the
limbs).
▪ a. AC is an autosomal
dominant genetic disorder
caused by a missense
mutation in the FGFR3
gene for the fibroblast
growth factor receptor 3.
 Disorders of extracellular
matrix
• Osteogenesis imperfecta (OI).
OI is a group of disorders (types
I-VII) with a continuum ranging
from perinatal lethality → severe
skeletal deformities → nearly
asymptomatic individuals.
• a. OI (types I-IV) are autosomal
dominant genetic disorders
caused by mutations in COL1A1
gene and COL1A2 gene for type I
procollagen proteins

• (we already went into this earlier in

the semester so I’m not going through
it in detail)
 Ehlers Danlos syndrome (EDS)
• EDS is an autosomal dominant
genetic disorder caused by
mutations where at least two
different genes have been
implicated thus far:
▪ i. COL5A1 gene for Type V
procollagen
▪ ii. COL5A2 gene for Type V
procollagen
• 50% of EDS affected individuals
inherit a mutant gene from an
affected parent whereas 50%
have a de novo mutation.
• Prevalence. The prevalence of
EDS is 1/20,000 births *very
underdiagnosed!*

Actually more like 1 in 500 in the UK: https://bmjopen.bmj.com/content/9/11/e031365

 Marfan syndrome
• MFS is an autosomal
dominant genetic disorder
caused by a mutation in the
FBN1 gene for the fibrillin-1
protein, which is an essential
component of microfibrils
found in both elastic and
nonelastic tissue.
• Microfibrils play a role in the
formation of the elastic
matrix (i.e., elastic fibers),
elastic matrix-cell
attachments, and the
regulation of growth factors.
• Prevalence. The prevalence
of MFS is 1/5,000 to 10,000
births.
• Several genes are
associated with
Hirschsprung disease.
• In all cases the gene
products take part in the
migration and maturation
of intestinal neural
precursors.
• The inheritance pattern is
usually autosomal
dominant if caused by a
mutation, with
incomplete penetrance
(50% to 70%).
• Nearly 12% of all patients
with Hirschsprung
disease have a
chromosome disorder,
most commonly trisomy
21.
 Etiology of Cardiac Defects
• Estimates for risk of cardiac defects are based on the
assumption that approximately 80% of all congenital
cardiovascular abnormalities are multifactorial.
• Currently, only one in five cardiac defects has a clearly identified
pathogenetic cause.

• About 15% to 20% of congenital cardiac defects are caused

by chromosomal aberrations (including copy number
variants).
• Approximately 3% to 5% are caused by single-gene defects;
• and 1% to 2% by teratogenic exposures during pregnancy.

• The evaluation of a congenital heart defect should therefore

always include a detailed family history;
• a detailed history of possible infections during pregnancy;
• and a detailed history of teratogenic exposures (alcohol, drugs,
medications, and chemical substances).
 Noonan Syndrome
• Noonan syndrome is an autosomal dominant condition, (usually
deletion of PTPN11) which is characterized by
• short stature,
• distinctive craniofacial features,
• congenital cardiovascular disease,
• and other clinical findings such as developmental delay and
intellectual disability, lymphatic abnormalities, and genito-urinary
abnormalities.
• Although Noonan syndrome occurs in 1 in 1,000 to 1 in 2,500 persons,
• individuals with Noonan syndrome may escape diagnosis if the
features are only mildly expressed.
 Hereditary Spherocytosis
In hereditary spherocytosis, the spleen destroys the abnormal spherocytes.

This hemolysis results directly in varying degrees of anemia (causing pallor and
fatigue), hyperbilirubinemia (causing jaundice)

• With a prevalence of 1 in 5,000, it is

the most frequent congenital
hemolytic anemia in central
Europe.
• In at least 75% of cases, the
spherocytosis is inherited as
autosomal dominant, and there is
one affected parent.
• The remaining 25% are either
inherited as autosomal dominant
with incomplete penetrance,
inherited as autosomal recessive,
or caused by new mutations.
• Hereditary spherocytosis is caused
by a variety of molecular defects in
the genes that are necessary to
maintain the normal shape of an
erythrocyte, which is a biconcave
disk.
SCD Pathogenesis and Genetics
• In adults, hemoglobin is a tetramer of two α-globin chains
and two β-globin chains coded by different genes.
• Sickle cell hemoglobin HbS occurs through a point
mutation in the sixth codon of the HBB gene coding for
the β-chain.
• A base switch from GAG to GTG (at the nucleotide level,
called mutation c.17A>T) results in an amino acid
substitution from glutamic acid to valine (at the protein
level, called mutation p.E6V).
• In the deoxygenated state, HbS clots and erythrocytes
take on a sickle shape, lose their flexibility, are
sequestered in the spleen and liver, and disintegrate.

• They obstruct capillaries and small

arterioles, which leads to organ
infarcts. Among the most affected
organs is the spleen
 α-Thalassemia
• Relatively rare in Western countries.
• They mostly occur in Southeast Asia, Southern China,
and the Middle East.
• α-globin is coded by two homologous genes (HBA1
and HBA2), meaning that there are a total of four
gene copies of α-globin.
• Both genes are positioned one after the other on
chromosome 16p13.3 and, thus, are normally
inherited as a pair.
• The severity of the clinical phenotype depends on
how many of these four gene copies are missing or
altered through mutation:
α-Thalassemia inheritance
 Thalassemia minima–
50% functionality
■ If only one gene copy is missing, this results in thalassemia M F
minima, which is clinically asymptomatic. HBA1 X
HBA2
■ If two gene copies are missing (genotype either –α/–α or – –
/αα, this results in thalassemia minor.
Thalassemia minor–
Affected individuals are often clinically asymptomatic but 50% functionality
have laboratory anomalies (mild microcytic anemia, mild M F
poikilocytosis, and anisocytosis). HBA1 X
HBA2 X
■ Absence of three gene copies is called HbH disease (– –/– or
α). M F
HBA1 X X
This leads to the formation of HbH (ββ/ββ) that precipitates
and forms intra-erythrocytic inclusion bodies. HBA2

Clinically these patients manifest variable degrees of

hemolytic anemia, and splenomegaly. HbH disease –
25% functionality
■ Functional loss of all four gene copies results in the most M F

severe form of α -thalassemia, Hb-Bart disease. HBA1 X X

It causes hydrops fetalis and is not compatible with life. HBA2 X

The few patients who are born alive usually die within a few
days. Hb-Bart –
This disorder is characterized by the formation of Hb-Bart, 0% functionality
a hemoglobin that is exclusively made up of β-globins M F

(ββ/ββ). HBA1 X X

It has high oxygen affinity and causes severe hypoxia of HBA2 X X

the peripheral tissues.

 β-Thalassemia – HBB gene
• Far more frequent than α-thalassemias.
• In the Mediterranean they belong to the most
frequent causes of anemia.
• Since there is only one gene and two gene copies
for β -globulin, there are only two types of β -
thalassemia:
• thalassemia minor (with heterozygosity, –/β)
and thalassemia major with homozygosity for a
mutation of the β-globulin –/–)
• Patients with β-thalassemia minor are clinically
asymptomatic or have only mild symptoms.
• Sometimes there is slight splenomegaly in addition
to mild anemia.
• Laboratory tests typically show mild microcytic
anemia (Hb 10 to 11 g/dl)
 β-Thalassemia
• β-Thalassemia major is a serious disease.
• Affected children are asymptomatic at birth, since HbF contains no β-
globin.
• At the age of 3 to 6 months, the infant develops progressive
hepatosplenomegaly and severe microcytic anemia (with anisocytosis and
poikilocytosis, poly-chromasia, and dacryocytosis (teardrop erythrocytes)).
• The excessive α-chains tend to aggregate and form insoluble
inclusion bodies in the erythrocytic precursor cells of the bone
marrow.
• Intramedullary hemopoiesis is significantly increased as well, which
results in bone changes.
• Among these are typical facial changes such as enlargement of facial
bones pathological fractures, growth defects, and typical radiological
symptoms (e.g., so-called “hair-on-end” appearance).
• Excessive intestinal iron absorption can result in hemo-siderosis with
subsequent pathology in the heart, pancreas, liver, and other organs.
β-Thalassemia Intermedia in a 13-Year-Old Girl.
A. Typical thalassemic facies with enlargement of
cheek bones and maxilla.
B. Distinct abdominal swelling from
hepatosplenomegaly.

β-Thalassemia Major. “Hair-on-end”

appearance of the skull.
β-Thalassemia inheritance
 Heritable Bleeding Disorders
• Hemophilias
• Within the large group of blood coagulation disorders, the
term hemophilia is applied to two X-chromosomal
heritable diseases:
• factor VIII deficiency (hemophilia A) and
• factor IX deficiency (hemophilia B)
• Blood clotting factor VIII has two functional subunits:
■ Factor VIII = antihemophilic globin, encoded by an X-
chromosomal gene
■ vWF = von Willebrand factor, carrier protein of factor
VIII, encoded by an autosomal gene (this is autosomal
dominant inheritance)
• A deficiency in factor VIII results in hemophilia A,
• while a deficiency in VWF results in von Willebrand
disease.
 Hemochromatosis
• Hemochromatosis is an iron
storage disorder,
• with iron overload in the body
(“siderosis”) resulting from excessive
iron absorption.
• A five-fold increase over normal iron
content results in organ dysfunction.
• HFE hemochromatosis is, genetically,
the most frequent autosomal
recessive disorder among Caucasians,
with a prevalence of risk genotypes of
up to 1 in 200 and a carrier frequency of
about 1 in 10 in various populations.
• Penetrance, however, is low, with
published data in the range of 1% to
30%.
• Men are 10 times more likely than
females to become symptomatic
(male:female ratio 10:1).
• The onset of symptoms is usually after
age 40 years.
 Cystic Fibrosis
• CF is an autosomal recessive disorder that is caused by
mutations in the CFTR gene
• The gene product, cystic fibrosis transmembrane
conductance regulator, is a chloride channel located in
epithelial cells (especially exocrine glands);
• More than 1,000 mutations in the CFTR gene have been
reported, but most of them are rare.
• By far the most frequent mutation in Caucasians is
Delta-F508 (p.F508del, traditionally denoted ΔF508).
• In this mutation, the loss of the three nucleotides CTT
causes the final gene product to have a deletion (Δ) of the
amino acid phenylalanine (F) at position 508 in the
polypeptide chain.
• The malfunctioning CFTR protein is labeled for
destruction before it can even reach the cellular
membrane
The condition is inherited in an autosomal codominant pattern.

Codominance means that two different versions of the gene may

be active (expressed), and both versions contribute to the genetic
trait.
Mutations in the SERPINA1 gene cause alpha-1 antitrypsin
deficiency. This gene provides instructions for making a protein
called alpha-1 antitrypsin, which protects the body from a
powerful enzyme called neutrophil elastase (produced during
inflammation).
Without enough functional alpha-1 antitrypsin, neutrophil elastase
destroys alveoli and causes lung disease. Abnormal alpha-1 antitrypsin
can also accumulate in the liver and damage this organ.

Environmental factors, such as exposure to tobacco smoke, chemicals,

and dust, likely impact the severity of alpha-1 antitrypsin deficiency.
The most common version (allele) of
This is an example of
the SERPINA1 gene, called M, produces
codominance:
normal levels of alpha-1 antitrypsin. M = normal (recessive)
S = moderate levels produced
Most people in the general population Z = little to no production
have two copies of the M allele (MM) in
each cell. Other versions of
the SERPINA1 gene lead to reduced
levels of alpha-1 antitrypsin.

For example, the S allele produces

moderately low levels of this protein,
and the Z allele produces very little
alpha-1 antitrypsin.

Individuals with two copies of the Z

allele (ZZ) in each cell are likely to have
alpha-1 antitrypsin deficiency.

Those with the SZ combination have an

increased risk of developing lung
diseases (such as emphysema),
particularly if they smoke.
 Genes are related to Parkinson
disease
• Most cases of Parkinson disease probably result
from a complex interaction of environmental and
genetic factors.
• These cases are classified as sporadic and occur in
people with no apparent history of the disorder in
their family.
• The cause of these sporadic cases remains unclear.
• Familial cases of Parkinson disease can be caused
by mutations in the LRRK2, PARK2, PARK7, PINK1, or
SNCA gene, or by alterations in genes that have not
been identified.
• Mutations in some of these genes may also play a
role in cases that appear to be sporadic (not
inherited).
 Causes of AD
• The two main types of AD are early-onset
(familial) and late-onset (sporadic).

• Early-onset AD is rare, usually affecting people

aged 30 to 60 and usually running in families.
– Identified mutations in three genes that cause early-
onset AD.

• Late-onset AD is more common. It usually

affects people over age 65.
– identified a gene, apolipoprotein E (ApoE). Believed
this protein is involved in the formation of beta-
amyloid plaques.
 Familial Alzheimer’s Disease
• Familial Alzheimer's disease is caused by any one of three
different single-gene mutations on chromosomes 21, 14, and 1.
• Each of these mutations causes abnormal proteins to be
formed.
• Mutations on chromosome 21 cause the formation of abnormal
amyloid precursor protein (APP).
• A mutation on chromosome 14 causes abnormal presenilin 1
(PSEN1) to be made, and a mutation on chromosome 1 leads to
abnormal presenilin 2 (PSEN2).

Nature Reviews Neurology 8, 598-600 (November 2012)

 Amyotrophic Lateral Sclerosis (Lou
Gehrig Disease)
• Incidence of ALS is 1 to 3 per 100,000 individuals. Approximately 1 in
10 patients with ALS has a positive family history.
• Autosomal dominant, autosomal recessive, and X-linked types of
ALS are known, and various disease-associated genes and
chromosomal susceptibility loci have been identified.
• The disorder causes muscle weakness and atrophy throughout
the body caused by degeneration of the upper and lower motor
neurons.
• Affected individuals may ultimately lose the ability to initiate
and control all voluntary movement.
• There is a known hereditary factor in familial ALS (FALS), where the
condition is known to run in families, although this accounts for
only around 5% of all cases.
• An inherited genetic defect on chromosome 21 (coding for
superoxide dismutase – SOD1) is associated with approximately
20% of familial cases of ALS.
 Duchenne and Becker Muscular
Dystrophies
• Duchenne muscular dystrophy (DMD) is the most frequent
muscular dystrophy.
• It was first described by Duchenne in 1868.
• Almost 100 years later (1955), Becker and Kiener described a
milder type that (as we know today) is caused by allelic
mutations in the same gene on the X chromosome.
• Both are recessive X-linked inherited disorders.
• This milder type was named Becker muscular dystrophy
(BMD).
• Incidence of DMD is about 1 in 3,500 male newborns.
• BMD in male newborns is much rarer,
• with an incidence of 1 in 18,000.

Pseudohypertrophy of the calves in Duchenne Muscular

Dystrophy. “Pseudo” implies there is no actual increase in muscle
tissue. The striated muscle has been replaced by connective
tissue and fat.
 Duchenne and Becker Muscular
Dystrophies

Duchenne Muscular Dystrophy often results from a frameshift mutation,

causing a truncated, nonfunctional form of dystrophin. Age of onset is 2-6
years old with poor prognosis.

Becker Muscular Dystrophy mutations are usually deletions of exons, however

the dystrophin has some functionality therefore symptoms are not as
severe. Age of onset is late childhood to adolescence, however some rare
cases have shown onset as late as 60!

https://compbio.berkeley.edu/people/ed/rust/Dystrophin.html
 Metabolic Disorders - PKU
• Phenylketonuria (PKU) is caused by a genetic deficiency
of the enzyme phenylalanine hydroxylase (PAH), which
catalyzes the conversion of phenylalanine (Phe) to
tyrosine
• This leads to a massive increase of Phe in the body and
progressive brain damage.
 Medical Genetics Block IV Outline Summer 2023
Dr. Stephanie E King

Please feel free to alter and highlight as needed – this is for you to help you be successful 😊

❖ Epigenetic Etiology of Disease and DOHaD

Note: I am highlighting only what I think the USMLE will test you on based on the various
textbooks, but I think that the epigenetics lectures in general are important background for
when we get into multifactorial inheritance
⮚ Human disease categories - It turns out that actually, things are a bit more complex than
we first learned.
▪ Some monogenic disorders can be impacted by other genes, causing incomplete
penetrance
▪ In addition, several diseases are polygenic
● Digenic disease - Consider two parents – Parent A and Parent B. Parent A and
Parent B both hold different genetic mutations, but are unaffected because the
only have the one mutation. Parent A passes down mutation A to their child and
Parent B passes down mutation B to the same child. When the child has both
mutations a disease suddenly manifests where one gene alone did not. This is
known as a true digenic disease.
▪ or environmental
● Obesity, for example, is a primarily environmental disease regardless of opinion
on the root cause (overnutrition, sedentary lifestyle, etc…).
♦ However, some people genuinely DO have a genetic predisposition, meaning
that they have a specific mutation. They are more prone to obesity than
others. But these individuals may not become obese unless they have certain
environmental conditions happen like a more sedentary lifestyle
♦ This would be an example of a multifactorial disease which is both genetic
AND environmental!
⮚ Nature or Nurture argument: Genetics or Environmental
(hint: it’s both – almost always both are important in disease etiology)
 ▪ Twin studies – allows us to determine how much is strictly genetic vs
environmental/lifestyle factors with a specific disease
● This is specifically identical twins so their genetic code is theoretically the same,
however their epigenome is different
♦ When twins are born, they have just shared the same environment in utero
with very little difference. Their epigenomes will be very similar
♦ However, as they age and get different environmental exposures and make
different lifestyle choices, their epigenomes start to differentiate. This helps
explain why one twin can die of cancer while another never gets cancer; one
twin has Crohn’s disease while another does not, etc
♦ This phenomenon is known as epigenetic drift

⮚ Epigenetics – the molecular biology aspects

▪ Epigenetics literally means above or around genetics. It is the study of heritable

changes in the cellular state that are not caused by changes in the nucleotide
sequence of the DNA
▪ DNA methylation – the addition of a methyl group on a CpG residue
● CpG is specifically referring to a cytosine that is followed by a guanine in a gene
sequence (p refers to the phosphate sugar backbone)
● Increased methylation levels associated with a specific gene decrease the level
of gene transcription
Decreased methylation levels associated with a specific gene increase the level
of gene transcription
● Areas of the genome can be hypermethylated (has above the expected amount
of methylation) or hypomethylated (has below the expected amount of
methylation)
♦ Hypermethylation – lots of Me groups – gene expression decreases

♦ Hypomethylation – fewer Me groups – gene expression increases

● DNA methylation is heavily involved in the process of genomic imprinting and
silencing genes in a parent-of-origin manner
● Agouti mice – in this example, the mice are genetically identical, however the
agouti locus has differential methylation of the gene
♦ Yellow coated mice have hypomethylation of this locus which keeps the gene
turned on. These mice are prone to obesity, cancer, and diabetes
 ♦ Brown coated mice have hypermethylation of this locus which turns the gene
off. These mice are thinner and healthier in general
▪ Histone modification – addition of chemical modifications to the lysine residues on
the histone tails
● Can have methylation, phosphorylation, ubiquitination, but we’re mostly going to
focus on acetylation
♦ Acetylation increases gene expression by reducing how tightly the DNA is
bound to the histones, freeing up the region to be transcribed
● Euchromatin refers to areas of the genome that are highly transcribed – these
areas are loosely packed and have lots of acetylation
● Heterochromatin refers to areas of the genome that have low or no
transcriptional activity. Densely packed with methylation modifications.
♦ Barr bodies are considered to be silenced by condensing into
heterochromatin
▪ Noncoding RNAs – Can include several different types of RNA including lncRNA,
siRNA, miRNA, piRNA, snoRNA, and tRNA. These are considered epigenetic because
they regulate posttranscriptional modification, gene expression, and the
preservation or destruction of mRNA transcripts.
● miRNA are small transcripts (21-25nt in length) that specifically either represses
translation or cleave mRNA to otherwise prevent translation
♦ In other words, miRNAs silence or repress genes

▪ All of these epigenetic marks/processes contribute to differential gene expression.

Effectively, if one group has significantly more or less of these marks targeting a
specific gene compared to a control group, their expression of that gene will likely
significantly change (either go up or down) compared to the control group.
● I.e. DNA methylation causes differential gene expression by repressing
expression of genes
● Histone acetylation causes differential gene expression by increasing expression
of genes
▪ Additionally all of these epigenetic marks tend to work together to produce gene
silencing or increase gene expression
● For example, in Fragile X syndrome, the CGG trinucleotide repeats cause a
silencing of the gene because they become hypermethylated. Additionally,
acetylation of histones for that gene become reduced in individuals with fragile
 X. DNA methylation silences the gene but histone deacetylation helps silence the
gene as well.
⮚ X Chromosome inactivation (XCI) – females must transcriptionally silence one of their X
chromosomes by turning it into a Barr body
▪ Occurs early in development. Any of the two chromosomes may become inactivated
in a generally random process. All daughter cells of that cell have the same X
chromosome inactivated
▪ Effectively this means that all females are mosaics expressing either the paternal
origin X or maternal origin X in different areas and cells of their body.
● The most obvious example of this are calico and tortoiseshell cats showing
expression of orange and black coat color depending on which X chromosome is
silenced
▪ The process of creating a Barr body is mediated by differential inactivation of the
gene XIST
● XIST stands for X inactivation-specific transcript which is on the X chromosome
● XIST produces a signal that causes increased DNA methylation on the X
chromosome this gene is activated on. This subsequently silences the grand
majority of the chromosome
▪ Not all loci on the chromosome are inactivated
● Some genes at the tip of the short arm (p) remain active
● If all loci on the X chromosome were inactivated, then all women would have the
clinical features of Tuner syndrome (or all Turner syndrome women would be
normal if this was physiologically normal)
● Additionally, more than one chromosome in a male with Klinefelter’s syndrome
would not cause any effect if all of the X chromosome was inactivated
▪ Theoretically some female carriers of the Duchenne Muscular Dystrophy gene show
evidence of DMD through elevated serum creatine kinase
● However, this is notoriously unreliable for testing because this varies depending
on XCI. If a female has more inactivation of the mutant chromosome, especially
in muscle cells, this may not present at all.
● Some females have mild or even full expression of DMD if the majority of their
mutant X chromosomes are active. This is known as skewed X-inactivation
because significantly more than 50% of the DMD chromosomes are active
♦ In fact, we think that X-chromosome inactivation patterns may be inherited
and not actually that random at all. Some families with DMD and Fabry
 disease have several affected females which would be exceedingly rare under
normal circumstances
⮚ Fabry disease – X-linked lysosomal storage disorder caused by a deficiency of
alpha-galactosidase A
▪ Symptoms and progression
● Vascular cells appear to be most affected and this disease can be adult-onset
● Purpura-type rash appears all over the skin, in the gums, and the eyes
● Other symptoms include proteinuria (kidney damage) which eventually results in
coronary disease, renal failure, and eventual death from cardiorenal disease
● As vascular cells are everywhere throughout the body, the organs affected and
general symptomology are highly variable. Usually this results in multi-system
failure
▪ Females with Fabry Disease – usually affects males and females are unaffected
carriers, however…
● Sometimes an X-inactivation pattern is not random and the distribution of cells
active vs non-active is not evenly distributed throughout the body
● There may be more cells in specific organs with the Fabry X turned on and fewer
cells with the healthy non-Fabry X active.
● This is due to differential methylation and imprinting, skewing X-inactivation
⮚ Genomic Imprinting

▪ Parent of origin effect - Different clinical features develop depending on if a gene

allele was inherited from the father or mother
● DNA methylation is the main mechanism of genomic imprinting – turns genes off
or leaves them on.
● This form of DNA methylation occurs very early in development in utero
▪ Uniparental disomy is the rare occurrence when an offspring inherits two copies of
a chromosome from a single parent and no copies from the other
● Cell is still 2n like normal, but this causes issues with imprinting
● Trisomy rescue - Sometimes this occurs in a cell that would be normally a
trisomy (i.e. 2n egg with 1n sperm or 1n egg with 2n sperm) but during the first
divisions of the embryo, that extra chromosome is lost.
♦ About 2/3rds of the time, this is results in a normal 2 chromosome state with
1 chromosome from the mother, 1 chromosome from the father. This would
be
♦ However 1/3rd of the time, this results in both chromosomes from the
mother or both chromosomes from the father
⮚ This uniparental disomy can cause issues like PWS and Angelman even
without the deletion involved because only the maternal or only the
paternal copies are present

⮚ Angelman syndrome is

▪ Caused by maternal deletion on 15q

▪ But also caused by paternal uniparental disomy (no maternal copies

of genes available)
⮚ Prader-Willi Syndrome is

▪ Caused by paternal deletion on 15q

▪ But also caused by maternal uniparental disomy (no paternal copies

of genes available)
⮚ Beckwith-Wiedemann Syndrome (BWS) – new disorder

▪ Another genomic imprinting disorder.

● This one is in 11p15.5
● Can be caused by both a maternal deletion of this area or
paternal uniparental disomy
▪ Causes overgrowth of several organs which results in a susceptibility
to certain cancers, congenital abdominal wall defects, hypoglycemia
from pancreatic issues, asymmetrical kidney problems, and an
enlarged tongue
 ▪ Rett Syndrome
● Occurs in 1 in 8500 girls. One of the most frequent heritable cause of intellectual
disability in females
● Causes breathing disturbances, impairment of sleeping patterns, progressive
scoliosis, and eventually neurodegeneration to an early death
● X-linked disorder with mutations in the MECP2 gene which binds to methylated
DNA in the human genome acting as a master regulator of gene transcription. If
this gene starts to malfunction, the transcription of thousands of genes is altered
⮚ Developmental reprogramming – An epigenetic mechanism allowing an organism to
respond to the surrounding environment during cell differentiation, changing the
phenotype and gene expression without modifying the genetic code
▪ The earlier the exposure to an adverse environment, the more an individual is
affected
● This is because in adults, all cells have differentiated for the most part, especially
in the brain. However in children or even fetuses, they still have a lot of
development left. If an environmental stressor hits them early in life, this can
disrupt normal epigenetic programming, permanently altering certain processes
like cell metabolism, survival, proliferation, and activity
▪ This can lead to cardiovascular disease, metabolic syndrome phenotypes, and
changes in neurological disease
● In extreme cases, this can even change brain volume!!

❖ Trinucleotide Repeat Expansions

⮚ Dynamic Mutations – most dynamic mutation diseases are caused by the expansion of
trinucleotide repeats
▪ Threshold length – below a certain threshold number of repeats, the repeat
sequence is stable. If the number of thresholds bypasses this threshold and is passed
down to future generation, this cases disease
● Premutation status – this is a status of subclinical disease. A person may be
phenotypically normal but be very likely to pass down an expanded gene to their
children, causing disease in the offspring
▪ Anticipation - Additionally, this instability causes the repeats to be expanded even
further, getting progressively worse with each generation
● This also means that with each generation there will be an earlier age of onset
and the disease will also become more severe
 ● Additionally, this can also cause an increase in disease penetrance with many
diseases like Huntington’s having 100% penetrance
▪ Trinucleotide repeat expansion
● Expansion of simple sequence repeats (SSRs) also called microsatellites
♦ These are repeat units of 1-6 nucleotides that are abundant throughout the
human genome that normally don’t cause any issues
♦ Depending on the location of the unstable, expanding repeat sequence, the
amplification can affect the expression of one or more genes
⮚ This could cause a production of an altered protein

▪ Lowest threshold of expansions before it causes disease

▪ This would occur if the expansion was within the coding sequence
● Huntington’s Disease
● Some spinocerebellar ataxias
⮚ An accumulation of expanded pre-mRNA or mature mRNA molecules

▪ Higher threshold of expansion

▪ Pre-mRNA would be expansion of introns

● Friedreich’s ataxia
▪ Mature mRNA would be in the other intergenic regions, especially
either the 5’ end or poly A tail.
● If this 5’ untranslated area is affected, this can actually prevent
transcription because of methylation close to the promoter
♦ Fragile X
● If the 3’ polyA tail is disturbed, for example, this means it cannot
leave the nuclear envelope
♦ This is what happens in Myotonic dystrophy type 1

♦ Root cause of expanded repeats

⮚ During DNA replication, the single strands can cause hairpin loops,
especially for trinucleotide repeats with cytosine and guanines (CGG,
CAG, etc). Cytosine and guanine are prone to want to bind together and
their bonds are strong (triple hydrogen bond)
 ▪ This causes misrepair and expansion when DNA polymerase tries to
repair its “mistakes” and synthesizes more and more trinucleotide
repeats into the sequence
▪ This gets progressively worse because the longer the repeat
sequence, the more hairpins can occur during DNA replication!!!
♦ Sex-specific expansion – repeat expansion differs depending on if it occurs
during oogenesis or spermatogenesis in certain disorders
⮚ In Huntington Disease, repeat expansion usually occurs during
spermatogenesis
⮚ In Fragile X, repeat expansion occurs through oogenesis

⮚ In Myotonic Dystrophy, expansions occur through both spermatogenesis

and oogenesis, but larger expansions occur in oogenesis
⮚ Specific Expansion Diseases

▪ Huntington Disease (Huntington’s chorea)

● Autosomal dominant and caused by a CAG repeat expansion within the coding
region which changes protein sequence. Normal allele is <26 repeats and full
mutation disease starts at 40+ repeats
♦ Expansion occurs more often in spermatogenesis
● Males and females are equally affected
● Onset of disease typically occurs between 30 and 50 years, but can occur prior to
the age of 20. Symptoms include movement disturbances (chorea), cognitive
disturbances, and psychiatric abnormalities (including depression and rarely
psychosis). Atrophy of the basal ganglia eventually occurs.
♦ Average age of death is 54-55 years and most commonly occurs from
aspiration pneumonia from severe dysphagia
▪ Spinocerebellar ataxias
● Autosomal dominant and caused by a CAG repeat expansion within the coding
region which changes protein sequence. Repeat numbers depend on subtype
(range from SCA1 to SCA31)
● Causes degeneration of both the spine and cerebellum like the name sounds.
Balance issues are a common first sign.
▪ Fragile X syndrome
 ● X-linked dominant and caused by a CGG repeat expansion within the 5’ UTR of
the FMR1 gene which causes hypermethylation of the gene, preventing
transcription. Normal allele is 5-40 repeats and disease status starts at 200+
repeats
♦ Expansion occurs during oogenesis
● One of the most common causes of inherited intellectual disability. Clinical
diagnosis includes an elongated face, large ears, large testes, and autism.
♦ More common in males than females

♦ Intelligence problems can range from mild learning disability to severe

intellectual disability. It’s possible that intellectual impairment is the only sign
♦ Social and emotional problems as well as speech and language affected

♦ Classic triad of Fragile X syndrome is long face, prominent ears, and

macroorchidism
▪ Myotonic dystrophy
● Autosomal dominant and caused by a CTG repeat expansion within the 3’ UTR
region of the DMPK gene which prevents the mature mRNA from leaving the
nuclear envelope, instead accumulating in the nucleus. Normal allele is 5-34
repeats and disease status starts at 50+ repeats
♦ Can expand in both spermatogenesis and oogenesis, however oogenesis
results in much larger expansions
● Causes progressive muscle wasting and weakness often starting in the 20s and
30s. First signs are often prolonged muscle contractions (myotonia) where they
are not able to relax their muscles after use
♦ Ex: they can’t release their grip on a doorknob or handle. They may also have
locking of the jaw which causes slurred speech
● Facial muscles eventually become wasted and cause a narrow face with hollowed
cheeks with a slack expression. Can also cause mild to moderate intellectual
disability with hypogonadism, cardiac arrythmias, pulmonary issues, and
cataracts. One of the main physical appearance changes is frontal balding
♦ Eventually these individuals have cardiac arrhythmias with conduction
defects
▪ Friedreich ataxia
● Autosomal recessive (one of the very few instances!!!) and caused by a GAA
repeat expansion within the intronic region of FXN which causes an
 accumulation of pre-mRNA within the nucleus – only a small percentage of the
frataxin mRNA is correctly spliced and translated. Normal allele is 5-33 repeats
and disease status starts at 66+ repeats
● Onset of the disease is unfortunately pediatric – usually 10-15 years of age but
can be any point before 25 years old.
● Spinal cord and peripheral nerves degenerate and become thinner in addition to
a degree of cerebellar degeneration. This affects balance and movement, causing
awkward, unsteady movements as well as impaired sensory functions
♦ Eventually, this affects the autonomic nervous system, causing issues with
regulating the heart and may also cause diabetes due to autonomic
dysregulation

❖ Complex and Multifactorial Inheritance

⮚ Genetic disorders – defined by the onset of clinical symptoms caused by a specific

mutation or allele
▪ All disorders are caused by the interplay of genetic and non-genetic factors. Very
rarely are disorders just genetic or just environmental
▪ Additionally, monogenic diseases are rare. Most genetic diseases are polygenic,
having a cumulative effect of multiple disease alleles in addition to environmental
influence on the progression of disease
● Ex: coronary artery disease can be linked to a multitude of genes, but lifestyle
and environmental factors are primarily seen as inducing the disease
⮚ Multifactorial diseases

▪ These disorders do not follow a clear inheritance pattern and instead are caused by
the interplay between several genes (polygenic disease) and exogenous
(environmental) factors
▪ Common traits of Multifactorial Diseases
● These diseases can occur in isolation, with affected children born to unaffected
parents – no clear Mendelian pattern of inheritance
● Environmental influences can increase or decrease the risk of disease
● This disease occurs more frequently in one gender than the other, but it’s not
sex-limited
♦ First-degree relatives of individuals belonging to the more rarely affected
gender have a higher risk of having the disease
 ● The disease occurs more frequently in a specific ethnic group, but it is not
limited to any specific ethnicity
▪ Polygenic factors
● Multifactorial diseases have a large number of genetic factors, each making only
a small contribution to the final phenotype
● Inheritance is controlled by many genes with cumulative/additive effects in
addition to the environment
♦ No one gene is dominant or recessive to the other – they just add onto the
risk
● Genetic threshold
♦ Several human characteristics are polygenic and show a normal distribution,
evenly distributed about the mean
♦ One theory is that disease develops and is expressed only after a specific
critical liability threshold is reached.
⮚ The further this threshold is surpassed, the more severe the disease
phenotype becomes
⮚ However, if an individual does not reach this liability threshold, they do
not develop the disease
⮚ The threshold of genetic predisposition often differs between males and
females causing a disease disparity
♦ Risk of recurrence mathematical model:
The risk of recurrence for first-degree relatives approximates to the square root of the general
population incidence:
𝑅𝑖𝑠𝑘 𝑜𝑓 𝑟𝑒𝑐𝑢𝑟𝑟𝑒𝑛𝑐𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑑𝑒𝑔𝑟𝑒𝑒 𝑟𝑒𝑙𝑎𝑡𝑖𝑣𝑒𝑠 = 𝑖𝑛𝑐𝑖𝑑𝑒𝑛𝑐𝑒 𝑖𝑛 𝑔𝑒𝑛𝑒𝑟𝑎𝑙 𝑝𝑜𝑝𝑢𝑙𝑎𝑡𝑖𝑜𝑛

▪ Multifactorial inheritance – factors that increase the probability of recurrence in a

particular family
● Close relationship to the proband
♦ The proband is defined as a person serving as the starting point for the
genetic study of a family
♦ Terminology for relatives:

⮚ First-degree: parents, siblings, and offspring

 ⮚ Second-degree: grandparents and grandchildren, uncles and aunts,
nephews and nieces, and half-siblings
⮚ Third-degree: first cousins, great-grandparents, great-grandchildren
● High heritability of the disorder
♦ Heritability is defined as the proportion of the total phenotypic variance of
a condition that is caused by additive genetic variance
⮚ Often depicted using the symbol h2 and expressed as a proportion or
percentage
⮚ Ranges from 0 to 1. If H=0 then disease is entirely environmental; if H=1
then variation is entirely genetic
⮚ Heritability increases as the concordance of monozygotic twins increases

⮚ Heritability is estimated from the degree of concordance between

relatives
▪ However, keep in mind that not all genetic patterns have 100%
penetrance, environmental conditions may change the development
of disease, and epigenetic effects can alter the genetic expression,
changing the phenotype in identical twins so this may not be all that
accurate
● Proband of the more rarely affected sex
♦ If an individual of the rarer gender is affected by the disease, they must have
a particularly strong genetic susceptibility
● Severe or early onset disease
♦ The more severe the manifestation of a multifactorial condition, the greater
probability of recurrence
● Multiple family members affected
♦ Incidence in relatives is lover than for single gene disorders but higher than
the general population
♦ Incidence is much lower in more distance relatives
● Family studies of different multifactorial diseases
♦ Cleft lip – unilateral cleft lip alone (without cleft palate) is most mild form
while bilateral cleft lip and palate is a more severe form
 ⮚ If an individual has unilateral cleft lip, it is less likely that they will have a
sibling with cleft lip/palate. However, if they have bilateral cleft lip and
palate (more severe), the risk to subsequent siblings more than doubles!
♦ Pyloric stenosis – congenital narrowing of the pylorus, preventing food and
other stomach contents from passing into the duodenum
⮚ Has a male to female ratio of 5:1

▪ Recurrence risk is greater if proband is female

● Ex: If the initial child of interest (proband) is male, recurrence in
brothers is 3.8% and sisters is 2.7%. However, if the initial child is
female, the recurrence rate in her brothers is 9.2% and recurrence
rate in sisters is 3.8%.
● If a female is affected with pyloric stenosis, she must have a
particularly strong genetic susceptibility
⮚ If a parent has pyloric stenosis, then an infant has up to a 20% risk of
developing it
⮚ Affects about 3 out of 1,000 babies in the US and is generally more
common in Caucasian infants
▪ Sex-influenced and sex-limited traits – this is not the same as sex-linked traits
● These are traits that are autosomal
● Sex-influenced – traits that are expressed differently in the two sexes.
♦ Ex: Male patterned baldness

⮚ The allele is influenced by the androgens testosterone and

dihydrotestosterone, however only when the two hormone levels are
high
⮚ Males have a much higher level of these hormones than females
generally so the baldness allele has a stronger effect in males than
females
▪ There can be exception in instances where a condition causes
increased androgen expression in females
● Sex-limited traits – only occurs in one sex in healthy individuals
♦ Both males and females carry genes for lactation, however generally only
lactating females express these genes
 ⮚ However, anything that causes hyperprolactinemia (increased levels of
serum prolactin) can cause milk production aka galactorrhea. For
example, prolactinomas, a type of pituitary tumor.

❖ Genetic Linkage and Genome-Wide Association Studies (GWAS)

⮚ Genetic linkage

▪ Genetic polymorphism - the occurrence in a population of two or more genetically

determined forms (alleles sequence variance, etc)
● Types of polymorphisms
♦ Restriction fragment length polymorphisms (RFLPs)

⮚ These are palindromes recognized by restriction endonucleases. One site

may be present in some individuals but absent in others (present is one
allele; absent is another)
♦ Variable number of tandem repeats (VNTRs)

⮚ These polymorphisms result from varying numbers of repeats in a specific

region of a chromosome. The repeats can be 20-70 bases each and are
flanked by restriction sites. Depending on how many repeats there are,
the restriction fragments have varying size. This is what we use in DNA
fingerprinting!!
♦ Short tandem repeat polymorphisms (STRPs aka microsatellites)

⮚ Short repeats of 2-6 base long sequences. Often have many types of
alleles in the population, each allele having a different number of repeats
♦ Single nucleotide polymorphisms (SNPs)

⮚ Individual nucleotide positions where a point mutation occurred that is

heritable. SNPs are usually two-allele markers like what is seen in the
diagram. At this specific point, you either have a G or a C with G being
allele 1 and C being allele 2
▪ Genetic linkage is the quantification of how close two or more loci are on a
chromosome that sort together during meiosis crossover
● Crossover is the exchange of DNA between homologous chromosomes in
meiosis I
● Linkage is based on distance between genes
 ♦ Linked genes are close enough together that they do not segregate
independently during crossover (must be on same chromosome)
⮚ This violates Mendel’s third law- the principle of independent assortment
that states that members of different gene pairs assort to gametes
independently of one another
⮚ However, if two loci are positioned close together on the same
chromosome, these loci are inherited together more often than not
▪ It is still possible, but it only occurs at very low levels

⮚ Genes that are inherited together are called linked or parental (because
they’re inherited in the exact same combination as the parent’s
genotype)
⮚ Genes that are not linked are called recombinant

♦ Centimorgans (cM) are a unit of measurement for genetic linkage between

two loci
⮚ If two loci are 1 cM apart, cross-over occurs between them on average
only 1 in ever 100 meioses or 1% of the time
⮚ Keep in mind, this is not the same as physical distance

♦ Recombination occurs more frequently in certain areas (usually towards the

middle of chromosomal arms
⮚ However, recombination is much less frequent near centromeres and
telomeres meaning that linked genes are much more common in these
areas
● Linkage analysis – several steps need to occur in order to determine
♦ Establish linkage phase between disease-producing alleles

⮚ Effectively, figure out which alleles in genes of interest are most likely to
be linked based on inheritance patterns
♦ Determine if linkage exists between the two alleles

♦ If linkage exists, estimate recombinant frequency

 ⮚ Recombination Fraction – designated as θ, a measure of the distance
separating two loci or effectively, the likelihood that crossover
(recombination chromosome) will occur

▪
● Ex: If θ = 0.05, this means that on average, the alleles will
segregate together 19 times out of 10
♦ 95% of the time, these genes are inherited together

♦ 5% of the time, they are recombinant

⮚ Genes on the same chromosome with recombination frequencies < 50%

are said to be linked
▪ Linkage group = all known genes on the chromosome

⮚ Genes on the same chromosome with a recombination frequency of

about 50% are not linked
⮚ Logarithm of Odds scores (LOD scores) – do not worry about calculation,
this is only conceptual:
▪ If LOD score >3.0, there is statistical evidence of linkage

▪ If LOD score <-2.0, there is statistical evidence of non-linkage

▪ Anything between -2 and 3 is non-significant aka can’t be determined
one way or the other
▪ This is used to determine if our recombinant fraction is statistically
significant

⮚ Genome-wide association studies – examinations of many common alleles (usually

SNPs) in a population to determine if any are particularly associated with the
development of major diseases or traits
▪ Study design – usually case-control
 ● Compares two large groups of individuals – one healthy control group and one
case group affected by disease
● DNA is collected and the whole genome is assessed
● All individuals are then genotyped for the majority of commonly known SNPs to
see if any are significantly altered or associated in disease group
● Effect sizes of significant SNPs is reported using odds ratio
♦ Aka SNP 1 increases the probability of developing CVD by 1.5 or 150%
● The significant associations are represented by a Manhattan plot:

♦ X-axis is genomic location by chromosome and Y axis is basically looking at

how associated the genes are with the disease of interest
▪ Clinical application
● Personalized medicine – if we can determine someone’s genetic risk factors, we
can set up a personalized health plan to prevent symptoms from starting,
effectively prevent someone from getting the disease
♦ This could be preemptively starting medication, screening regularly, and
changing lifestyle factors
⮚ Ex: take alpha1 antitrypsin deficiency (that was the disease that caused
lung and liver failure) – many people never develop symptoms if they
happened to not be smokers or drink regularly. If we knew someone’s
genetic susceptibility to developing this disease, we could make sure they
know to never, ever smoke or they have a very high probability of dying
from lung failure
▪ Human Leukocyte Antigen (HLA) – the name of loci of genes that encode for the
major histocompatibility complex (MHC) in humans
● Haplotype – genes that are often inherited together – effectively they are very
strongly linked (strong levels of linkage disequilibrium)
 ♦ HLA complex genes have several genes that are inherited together in a
pattern that may increase the susceptibility to multiple diseases
● Genes residing on chromosome 6 that encode for cell-surface antigen-presenting
proteins. MHC genes specifically are human “self” antigens, effectively antigens
on the cell-surface that have a pattern recognized by the organism’s immune
system. The immune system learns to tolerate this pattern and know not to
attack it
♦ If something goes wrong with this mechanism (like a mutation), this can lead
to autoimmune or inflammatory diseases
● HLAs are incredibly diverse and this helps prevent a single disease from wiping
out the entire population
● HLA genes are the major cause of organ transplant rejections
♦ In order to find a good organ donor match, we match the patterns of each
individual’s HLA haplotypes
♦ The degree of rejection is proportional to the degree of disparity between
HLA haplotypes
● HLA subtypes
♦ HLA Class I (refers to MHC I)

⮚ Divided into:

▪ HLA-A

▪ HLA-B

♦ HLA Class II (refers to MHC II)

⮚ All start with D:

▪ HLA-DQ

▪ HLA-DR

▪ Inheritance of Type I diabetes

● Caused by the destruction of insulin-secreting β-cells in the islets of Langerhans
of the pancreas via autoimmune insulitis
♦ Results in absolute insulin deficiency
● Can be familial, but environmental factors play a bigger role
● Affected mostly by HLA class II genes: HLA-D (ex: DRB1, DQA1, DQB1, etc – not
necessary to memorize. Just know it’s HLA-D, not one of the HLA-A or HLA-B)
♦ Individuals with DR3 and DR4 have a 1 in 15 risk of developing type 1
diabetes compared with 1 in 300 in the general population so genetics can
actually affect susceptibility quite a bit
● Environmental factors
♦ Appears to have a link to seasonality – could this be infectious in origin due to
seasonal spread of disease?
♦ Immigrants assume risk of new country

⮚ If someone moves from a low T1D risk country to a country that has high
risk for T1D, their risk of developing T1D becomes high too. This implies
strong environmental risk
♦ Risk factors from case-control studies:

⮚ Infant and childhood diet – breast feeding is protective; transitioning to

cow’s milk at an earlier stage appears to increase risk
⮚ Several viruses can predispose, including maternal infection while in utero

⮚ Hormones, stress

⮚ Hygiene hypotheses – is a more “dirty” environment better for the

development of a child’s immune system? Are we using too much
antibiotic soap? Not letting the kids eat dirt? Maybe intestinal parasites
prevent autoimmune diseases by attenuating inflammation?
⮚ Vitamin D deficiency – known to cause immune issues
● Celiac disease – condition in which the immune system is abnormally sensitive to
gluten
♦ Can be ameliorated by a very strict, lifelong gluten-free diet

♦ Gluten causes immune system overactivity which causes a wide variety of

systemic symptoms
⮚ Initially thought to be caused by increased intestinal permeability
allowing gluten to leak from the intestinal lumen into the blood stream
where it is recognized and attacked by the immune system
 ⮚ Causes severe diarrhea, bleeding, weight loss, abdominal pain and
swelling in addition to other varying symptoms
⮚ Ultimately results in intestinal villi becoming blunted/destroyed which
prevents absorption of vital nutrients
▪ People with celiac disease can sometimes have exceedingly rare
vitamin deficiencies
● Sometimes this is the only clinical sign
♦ Prevalence is about 1 in 100 people worldwide

♦ Caused by MHC II haplotypes like HLA-DQA1 and HLA-DQB1

● HLA-B27-linked diseases
♦ MHC-I class surface antigen

♦ Associated with ankylosing spondylitis, psoriatic arthritis, inflammatory

bowel diseases (Crohn’s and ulcerative colitis), and reactive arthritis
♦ 90% of Caucasians with AS are positive for HLA-B27 therefore it is a common
diagnostic tool
⮚ However there are plenty of people with AS that do not have B27

▪ And 8% of Northern Europeans have HLA-B27 but only a fraction ever

develop one of these autoimmune diseases so this is certainly not a
prognostic marker!
⮚ This is especially true for people who are not ethnically European

⮚ Failure to understand this concept has caused a significant delay in

diagnosis for many individuals
♦ Having one of the HLA-B27 autoimmune diseases dramatically increases the
risk an individual will be diagnosed with another
⮚ Ex: people with AS often develop Crohn’s disease as well and vice versa

⮚ This is a phenomenon that is common to several different autoimmune

disorders. Having a single autoimmune disorder dramatically increases
the risk of having another autoimmune disorder, even if its risk comes
from a different HLA subtype
 ▪ This risk is generally thought to be about 25% but certain diseases are
clustered more than others like vitiligo and Hashimoto’s thyroiditis
▪ This could be due to certain haplotype patterns being inherited
together through genetic linkage

❖ Clinical Genetics I and II

⮚ Types of Human Birth Defects (Congenital Disease)

▪ Strict Definitions
● Malformation – a morphological defect caused by an intrinsically abnormal
(present from the beginning or early stages) developmental process
♦ Timepoint can be from the beginning of conception through early
embryogenesis and the beginning of organogenesis
♦ Can be genetic and/or environmental, ex: environmental if there is a
nutritional deficiency
♦ Diseases can include things like polydactyly and neural tube defects like spina
bifida
● Dysplasia – a morphological defect caused by an abnormal organization of cells
into tissues
♦ Timepoint for the birth defect is from early embryonic period through
organogenesis which may continue through pubertal development
⮚ Mind you, dysplasia is not always a birth defect. Dysplasia is often seen in
early stages of cancer – for example, the abnormal growth of cervical cells
that cause a positive pap smear
♦ Ex: Achondroplasia where chondrocytes are not being produced at adequate
levels, preventing bone elongation
● Disruption – A morphological defect caused by the breakdown or interference of
a normal developmental process
♦ Can occur at any time during gestation

♦ This is not genetic – environmental

 ♦ Ex: bowel atresia from vascular accidents causing one section of the bowel to
not develop from lack of blood supply or amniotic band disruptions where a
section of the sac wraps around a body part
● Deformation – a morphological defect caused by mechanical forces that interfere
with normal growth due to the position of the fetus in utero
♦ Occurs during the second and third trimester

♦ Strictly environmental

♦ Dislocation of the knee due to abnormal fetal position, clubfoot, abnormal

molding of the head, etc. This sometimes resolves by itself or may need
surgical correction along with special equipment to “retrain” the body
▪ Patterns of birth defects
● Sequence – A pattern of multiple defects derived from a single structural defect
or mechanical factor
♦ Ex: Potter sequence is caused by a single defect. Sometimes it can be an
obstruction of the ureter. Obstruction leads to hydroureter which leads to
hydronephrosis. The hydronephrosis leads to reduced fetal urine excretion.
This causes a reduced amount of amniotic fluid (oligohydramnios). This fluid
reduction causes fetal compression which leads to all sorts of limb and facial
deformities. All that from one single source – these events happen in
sequence
● Syndrome – a pattern of multiple defects that are pathogenetically related.
Multiple congenital defects happen at once which can then lead to subsequent
defects
♦ Ex: Down syndrome affects organogenesis from the very beginning and
affects multiple organs at once due to the increased gene dosage of trisomy
21. This results in congenital heart defects, intestinal blockage (duodenal
atresia, Hirschsprung, etc), issues with neurodevelopment… this is all from
that genetic syndrome cause, not like the cascade of events from that single
defect in a sequence.
● Polytopic field defect – these are defects in the development of the body plan.
♦ Ex: Abdominal wall defects, cleft lip/palate, neural tube defects,
holoproscencephaly
● Association – a pattern of multiple defects that occurs more often than expected
by chance alone, but appears to be idiopathic (for now) – we cannot classify this
as being part of a sequence or syndrome
 ♦ Ex: VACTREL association

♦ VACTERL Association – Occurs in about 1 in 10-20k newborns.

⮚ 5-25% of infants born with the VACTERL association die within the first
year
⮚ However, most malformations can be successfully treated surgically which
helps overall prognosis
⮚ Neurodevelopment/cognition does not appear to be affected

▪ Errors in determining body plan

● L/R Axis – involves the expression of the signaling protein SHH (Sonic hedgehog)
from the notochord, creating a baseline for what is determined to be the midline
of the body. After this point, organ patterning occurs.
♦ Situs inverus is the complete reversion or mirroring of organs which can be
caused by a defect in body planning
♦ Primary ciliary dyskinesia – an autosomal recessive genetic disorder
mutations in at least two genes: DNAH5 and DNAI1
⮚ Cause immotile or abnormally beating (dyskinesic) cilia.

⮚ Normally cilia are supposed to move rhythmically to move mucus from

the lungs to the throat, however if there are faulty cilia, mucus
accumulates
▪ This can cause issues with sinusitis and other respiratory infections

⮚ Sometimes this disease can coincide with situs inversus which is called
Karteneger’s syndrome
● Determination of anterior/posterior axis – involves a great number of regulatory
proteins called homeodomain proteins or homeobox (HOX) genes.
 ♦ Mutations in these proteins can range wildly in phenotype from very mild
disease to something severe enough where it is not compatible with life
⮚ Some experiments looking at gene function of these HOX genes caused
the body plan to completely change, causing fruit flies to sprout legs out
of their head instead of antennae
⮚ More mild forms can cause synpolydactyly or even something as simple
as hypodontia (congenitally missing teeth)
● Cleft Lip and Palate is a multifactorial genetic disorder associated with several
different mutations
♦ Mutations can include SHH which affects L/R axis but actually sometimes this
can be a homeobox-related gene like MSX and DLX as well. It depends on
what causes the palatine bones or palatine process not to adequately fuse
(It’s complicated and differs from one individual to the next).
▪ Connective tissue disorders
● Achondroplastic Dwarfism (achondroplasia) – a skeletal dysplasia with abnormal
growth patterning
♦ Autosomal dominant genetic disorder caused by a mutation in the FGFR3
gene (fibroblast growth factor 3)
♦ FGF is not able to stimulate growth of chondrocytes in the bones which
prevents normal bone elongation.
● Osteogenesis imperfecta – a group of disorders that prevent the hardening of
bones due to defective procollagen proteins
♦ There is a mix of autosomal dominant and other forms of inheritance (type
I-IV are autosomal dominant) and it is caused by a defect in the COL1A1 and
COL1A2 genes which code for type I procollagen
♦ Bones are weak, lacking adequate levels of compact bones which make them
very susceptible to breaking
● Ehlers Danlos syndrome (EDS) – stretchy skin; hyperflexible joints
♦ Autosomal dominant disorder associated with mutations in COL5A1 and
COL5A2 (among others) which code for Type V procollagen
⮚ There are multiple types of EDS which may have other genetic mutations
and patterns
 ♦ Can be heritable in 50% of cases, but 50% are also de novo mutations
● Marfan syndrome – Causes tall, thin individuals susceptible to cardiovascular
anomalies
♦ Autosomal dominant disorder caused by a mutation in the FBN1 gene which
codes for fibrillin-1, a protein essential for the structure of microfibrils
♦ Alters the formation of elastic fibers

▪ Congenital defects in the gastrointestinal system

● Hirschsprung Disease – causes immotility of the colon
♦ Most frequent cause of intestinal obstruction of newborns

♦ Boys are 4 times as likely to get this than girls

⮚ Recurrence risk is higher if proband is female

♦ An error of enteric neuron migration causes areas where there are very little
or no ENS ganglia
⮚ This causes a lack of peristalsis and stools cannot exit, causing a bowel
obstruction and ultimately megacolon. If this is left untreated, this can
quickly lead to death from bowel perforation and sepsis
♦ Usually autosomal dominant disease, however environmental causes are
indicated as well. About 12% of Hirschsprung disease cases are individuals
with Down syndrome or other chromosomal disorders
● Esophageal Atresia – causes a disconnection in the esophagus or may incorrectly
connect with the trachea (tracheoesophageal fistula)
♦ Usually associated with other birth defects (part of the VACTERAL
association)
● Duodenal atresia – caused by a lack of connection in between the duodenum
and jejunum.
♦ Induces epigastric fullness. Most dangerous aspect is immediate dehydration
because water cannot enter the small intestine to be absorbed.
♦ Between 20-30% of all cases are from Down syndrome

▪ Congenital heart defects

● Somewhat frequent in the population (7-8 out of 1000 births)
● No gender bias in development
 ● 80% of cases are multifactorial with most considered to be idiopathic (unknown
cause. 15-20% are chromosomal defects; 3-5% are monogenic diseases; 1-2% are
from teratogenic exposures
♦ Often associated with other malformations as well and one of the most
frequent chromosomal causes is trisomy 21
● 80% of individuals with Noonan syndrome have cardiovascular defects
♦ Autosomal dominant condition seen also with:

⮚ Distinct craniofacial features, intellectual disability, lymphatic

abnormalities (webbed neck), and genito-urinary abnormalities
⮚ Wide range of severity where some individuals with a mild phenotype not
being diagnosed
⮚ Blood disorders

▪ Hereditary Spherocytosis
● Causes spherical blood cells called spherocytes
♦ These are very fragile and get broken down by the spleen

♦ Caused by a mutation in the genes necessary to maintain the RBC biconcave

disk shape
● Causes varying degrees of anemia and potentially jaundice
● About 75% of cases are autosomal dominant and 25% are autosomal recessive
▪ Hemoglobinopathies – inherited mutations which affect the globin genes
● Sickle cell anemia
♦ Autosomal recessive caused by a point mutation in the β-chain (HBB)

⮚ A base switch of GAG to GTG causes a substitution of glutamic acid to

valine which causes a significant change in protein shape
● Thalassemias – caused by an issue in hemoglobin synthesis of globin chains,
malforming RBCs
♦ α-Thalassemia – caused by a mutation in α-globin

⮚ α-globin is encoded by HBA1 and HBA2 and as a result, there are four
copies of the gene available
▪ These genes show genetic linkage and are inherited as a pair
 ⮚ Seen more in SE Asian and Middle Eastern populations

⮚ Depending on how many copies of these four genes are missing, this can
cause different levels of disease
▪ If 1 copy is missing, this is thalassemia minima, an asymptomatic
carrier condition
▪ If 2 copies are missing, this is thalassemia minor, causing minor levels
of anemia which usually don’t cause symptoms, but are detected on a
blood test
▪ If 3 copies are missing, this causes thalassemia major (HbH disease)
which causes severe anemia among other issues
▪ If all 4 copies are missing, this is causes hydrops fetalis, a condition
not compatible with life
● The reason is because α-globin is used as a part of fetal
hemoglobin (HbF). If there is no α-globin, the fetus will not survive
as a result.
♦ β-Thalassemia – caused by a mutation in β-globin

⮚ β-globin is encoded by only one gene, HBB

⮚ Much more frequent than α-thalassemia, affecting primarily

Mediterranean populations (Greek, Turkish, and North African
populations i.e. Algeria, Tunisia, Morocco)
⮚ Depending on if one or both copies of this gene are missing, this can
cause different levels of disease
▪ If 1 copy is missing, this causes thalassemia minor, causing minor
levels of anemia which don’t usually cause symptoms, but are
detected on a blood test
▪ If 2 (both) copies are missing, this causes thalassemia major, a severe
anemia which requires blood transfusions
● Children with β-thalassemia major are asymptomatic at birth
because HbF does not have β-globin. However, as HbF becomes
exchanged for HbA, the anemia becomes progressive, causing
hepatosplenomegaly and severe anemia
▪ Heritable bleeding disorders
 ● Hemophilias – X-linked recessive disorders with individuals that are unable to
clot properly
♦ Hemophilia A – caused by factor VIII deficiency

⮚ More frequent of the two hemophilias

⮚ Very rare in females, but could theoretically happen if there is Turner

syndrome or skewed X inactivation
♦ Hemophilia B – caused by factor IX deficiency
● Von Willebrand Disease (VWD) – caused by a mutation of the von Willebrand
Factor (VWF) gene.
♦ Most frequent congenital clotting disorder – may affect up to 1% of the
population and tends to be underdiagnosed
♦ This is an autosomal gene (chromosome 12) which means that females can
have VWD as well
⮚ I was incorrect when I said it was a subunit of factor VIII and I misread the
book/slide – this is instead a carrier protein, vital for the function and
stability of factor VIII as it flows through the circulatory system (sorry, my
bad – they are absolutely functionally related though and VWD causes
issues with factor VIII clotting!!)
⮚ Hemochromatosis – an iron storage disorder

▪ Most commonly caused by an autosomal recessive mutation in the HFE gene

● However, disease penetrance is really low (1-30%) which implies there must be
other factors involved
▪ Causes elevated levels of iron (siderosis) which can cause organ dysfunction, starting
with the liver
▪ Men are 10 times more likely to get this disease than women

⮚ Respiratory System Disorders

▪ Cystic Fibrosis
● Most frequent autosomal recessive heritable disorder in North America and
Europe
♦ Highest incidence level is in Ireland
 ● Caused by a mutation in the CFTR gene which codes for a chloride channel
necessary for proper functioning of exocrine glands
♦ Most frequent mutation is Delta-F508/p.F508del which is a deletion of
phenylalanine at amino acid position 508
♦ In this instance, it causes malfunction/misfolding of the protein which is
subsequently labeled for destruction before it reaches the cell membrane
● Causes insufficient hydration of exocrine secretions due to a lack of ion transport.
♦ In the lungs, this cases mucus to be incredibly thick, preventing it from being
moved by cilia. This strongly predisposes people with CF to respiratory
infections
♦ In the pancreas, this blocks the pancreatic ducts, causing pancreatic
insufficiency, preventing both digestion and proper insulin availability
▪ Asthma
● Most frequent chronic childhood disorder in North America (and likely several
other areas in the world as well)
● Causes airway constriction (bronchospasm) triggered by exercise, airway
irritants, and/or allergies
● Associated with other atopic disorders like allergic rhinitis/sinusitis and atopic
dermatitis (eczema)
♦ All are caused by excessive production of IgE
● There is a strong hereditary component with about 50% twin concordance rate
♦ However, it is heavily linked to environmental pollutants like wildfire smoke
and industrial emissions in both origin and severity
▪ Chronic Obstructive Pulmonary Disease (COPD) – causes persistent blockage of
airflow from the lungs
● Risk factors are largely environmental from tobacco use, second hand smoke
exposure, air pollution, and chronic infections
● However there can be genetic causes as well
● α1-antitrypsin deficiency – is one genetic cause of COPD
♦ Caused by a mutation in the SERPINA1 gene (codes for α1-antitrypsin),
which has a protective effect from the inflammatory neutrophil elastase in
healthy individuals
⮚ Neutrophil elastase is meant to destroy bacteria but can be
inappropriately released if irritants cause an inflammatory response.
 ⮚ If there’s no α1-antitrypsin, the elastase can harm normal cells in both
the lungs and liver
♦ This is inherited in an autosomal codominant pattern.

⮚ The normal allele is termed M; the severe allele is Z. If an individual has

two copies of the Z allele, they can develop very severe disease
⮚ Neurological and Muscular Disorders

▪ Parkinson Disease (PD) – causes tremor

● Usually sporadic (likely environmental), but a certain subset of individuals have a
family history
♦ Genes related to familial disease:

⮚ SNCA – a competitive inhibitor for tyrosine hydroxylase. If there is a

malfunction in this pathway, L-DOPA can not be produced and therefore
no dopamine
⮚ PARK2 – codes for parkin, important in the ubiquitin-proteasome
pathways and a mutation may prevent proper recycling of defective
proteins
● Causes apoptosis in dopaminergic neurons in the substantia nigra
♦ Dopamine is essential for fine muscle movement, thus why these individuals
are affected by tremor
▪ Alzheimer’s Disease (AD)
● Most common form of dementia that can be both familial and sporadic
♦ Familial (Early onset) – involves several different genes, but especially a
mutation on chromosome 21 which codes for amyloid precursor protein
(APP)
⮚ It is thought that this may be the main reason why people with trisomy 21
ultimately develop Alzheimer’s – there is an increased dosage of the APP
gene
♦ Sporadic (Late onset) – may involve a defect in apolipoprotein E (APOE)
which is involved in the development of beta-amyloid plaques
 ⮚ Very likely environmental and lifestyle factors involved as well.
Uncontrolled diabetes, for example, can cause brain damage and
predispose an individual to vascular dementias as well as AD
● Caused by an accumulation of beta-amyloid plaques and/or tau protein tangles
▪ Amyotrophic Lateral Sclerosis (ALS)
● Low incidence – about 1-3 per 100k individuals
● Can have positive family history, but the disease is so rare that it’s difficult to
study exact etiology in populations
● Causes muscle weakness and atrophy due to the degeneration of motor neurons
which ultimately leads to an inability to initiate and control voluntary movement
▪ Autism Spectrum Disorders – a complex neurodegenerative disorder that causes
multiple symptoms in a spectrum
● Autistic people have difficulty interpreting social cues, difficulty with verbal
communication (may be fully non-verbal but may also be unaffected), and have
repetitive behaviors and hyperfixations
♦ There is a high level of variability from person to person on how much they
are affected – this is why it is designated autism spectrum disorders
● High level of prevalence – 1 in every 44 children according to latest CDC numbers
● Boys 4x more likely to be diagnosed than girls
♦ Some advocates and researchers argue that girls may be underdiagnosed
● High correlation to other mental disorders and physical illnesses
♦ Some individuals with autism have what is designated as syndromic autism,
autism that is part of an overall syndrome
⮚ Examples include fragile X and Rett syndromes

♦ Most are idiopathic, however (90+%)

● There are about 100-200 genes that have been linked to autism and it’s hard to
narrow down which ones are more relevant than others
♦ However most of them have to do with neurodevelopment, especially
alterations of glutamatergic and calcium signaling pathways
⮚ This would imply altered levels of neural excitability (could explain
sensory issues)
♦ Additionally, neuroimaging has demonstrated that there is altered brain
connectivity, a change in dendritic/axonal connection density
 ⮚ i.e. their brains are literally wired differently than people who are
“neurotypical.”
▪ Schizophrenia – a mental disorder characterized by alterations of thinking and
emotional responses
● Symptoms include paranoia, auditory and visual delusions, disorganized thinking
♦ On the opposite spectrum, some individuals experience catatonia with lack of
emotion and motivation with significant reduction in motor movement
● Relatively frequent in the population at 1%, affecting men and women equally
● Highly heritable with 80-85% genetic contribution
▪ Duchenne and Becker Muscular Dystrophies
● X-linked recessive disorders with mutation of the DMD gene which codes for
dystrophin
● Causes a breakdown of muscle tissue which is eventually fatal
♦ Dystrophin is important for the stability of muscle cells. If this protein is
faulty, it causes tears in the plasma membrane, causing uncontrollable ion
flux and apoptosis
● There is a wide variety of type of mutation (exon vs splice site vs point mutation
etc)
♦ If the mutation allows some degree of healthy dystrophin to be produced,
this causes the more mild form of the disease, Becker Muscular Dystrophy
⮚ Metabolic disorders

▪ Phenylketonuria (PKU)
● Caused by a genetic mutation in the PAH gene which codes for phenylalanine
hydroxylase
● Causes a toxic accumulation of phenylalanine in the boxy which leads to brain
damage
♦ Brain damage is progressive where each week that PKU is left untreated in
the first year of life, there is 1 IQ point lost
♦ If PKU is treated by diet restriction immediately, individuals can be
completely asymptomatic with no cognitive defects
♦ Can also cause a deficit of downstream metabolites like tyrosine, which can
affect dopamine synthesis in addition to other neurotransmitters/hormones
● Incidence levels are highest in Ireland and Turkey