Session 1
HBM3205
Clinical Genetics and
Inheritance
Cellular Basis of Disease Dr Sean Yan
Segregation and Independent Assortment
Mendel’s study of modes of inheritance
of disease formulated two laws:
Principle of segregation
• Homologus genes separate during
reproduction and each cell carries only
one of the homologus genes
Principle of independent
assortment
• Heredity transmission of one gene has no
effect on the transmission of the other
Mendelian
Autosomal dominant
Autosomal Recessive
X Linked Dominant
X linked Recessive
Y linked Patterns of
Non-Mendelian Inheritance
Incomplete dominance
Co-dominance – multiple alleles
Polygenic – multiple genes
Traits in humans are traced by constructing
pedigrees that follow traits through generations
Pedigree construction
• A diagram listing the members and ancestral
Pedigrees relationships in a family
• Uses a standard form and symbols
• Uses family history to show how a trait is
inherited and estimate risk for family members
• Provides genetic counseling for those at risk of
having children with genetic disorders
Numbering System Used in Pedigree Construction
Each generation is identified by a Roman
numeral
Each individual within a generation is
identified by an Arabic number
The first affected family member who
seeks medical attention for a genetic
disorder in referred to as the proband
Aborted or stillborn
Male offspring
Female
Deceased offspring
Mating
Mating between
relatives Unaffected individual
(consanguineous)
Parents and children. Roman Affected individual
I numerals symbolize
generations. Arabic numbers
II symbolize birth order within Proband: first in family that
generation (boy, girl, boy) was identified
1 2 3
P P
Known heterozygote
Monozygotic twins
Carrier of x-linked recessive trait
Dizygotic twins
Infertility
Offspring of unknown sex
Fig. 3-16, p. 60
Following a Trait Through a Pedigree
Fig. 3-17, p. 61
Pedigree Analysis Reveals Mendelian Patterns
in Human Inheritance
Analysis of pedigrees using knowledge of Mendelian Pedigree
principles allows us to:
Analysis and
Determine whether the
Determine whether the Construction is
trait has a dominant or
recessive pattern of
gene in question is
located on an X or Y a Basic
inheritance
chromosome or on an
autosome Method in
Human
This kind of
information can be
Genetics
used to predict risk
Patterns of Inheritance
Patterns in the pedigree are used to determine how a trait is inherited:
• Autosomal dominant
• Autosomal recessive
• X-linked dominant
• X-linked recessive
• Y-linked
Autosomal Dominant Inheritance
• The gene for the trait is on an autosome
• Phenotype shown by heterozygotes, individuals with one copy of the mutated
gene and homozygote individuals with two copies of the mutated gene
• Genetic risk
• Any child born to an affected parent has a 50% chance of inheriting it
• Heterozygote (affected) and unaffected parent will have a 50% of having a child
with the disorder
• Two affected individuals can have an unaffected child
Pedigree: An autosomal dominant trait
• Heterozygotes have an abnormal
phenotype
• If an affected individual is
heterozygous and has an unaffected
mate, each child has a 50% chance of
being affected
• Two affected individuals can have an
unaffected child
• Both sexes are equally affected and
capable of transmitting the trait
• Usually affected family member in
each generation
Fig. 4-6, p. 77
• Achrondroplasia
• Huntington’s Disease
Autosomal • Osteogenesis imperfect (collagen type I)
dominant • Marfan’s syndrome (fibrillin, found in
microfibrils)
disorders • Neurofibromatosis I (mutation in NF-1 which
inactivates ras) and II (tumours of 8th cranial
nerve)
Autosomal Dominant Disorders
• Though the individual carries the gene for the
Incomplete autosomal dominant
Penetrance • disorder, they do not show the phenotype
• Eg Retinoblastoma
• The variation in clinical features from person to
person is known as
Expressivity • variable expressivity
• Eg Neurofibromatosis
• The gene for the trait is on an autosome
Autosomal • Phenotype shown by homozygotes individuals
Recessive with two copies of the mutated gene
• Genetic risk: The offspring of heterozygous
Inheritance parents have a 25% chance of being affected
Autosomal Recessive Trait
• For rare traits, most affected
individuals have unaffected
parents
• All children of affected parents
are affected
• The risk of an affected child
with heterozygous parents is
25%
• The trait is expressed in both
males and females
Locus heterogeneity
• A disorder inherited in the same manner can be due to
mutations in more than one gene Eg Hearing
impariment/Deafness
Genocopies
Autosomal • Same phenotype due to mutation in different genes
recessive Phenocopies
trait • Same phenotype as a result of an environmental cause
Mutational heterogeneity
• Individuals who have different mutations at the same locus
are known as compound heterozygotes and they have
mutational heterozygosity
Non-Medelian Inheritance:
Incomplete Dominance
• Heterozygous individuals have a phenotype intermediate
between homozygous dominant and homozygous recessive
• Sickle-cell anaemia is a human example when aberrant
hemoglobin (Hb) is made from the recessive allele (s)
• SS = normal Hb is made
• Ss = sickle-cell trait (both aberrant and normal Hb is made)
• ss = sickle-cell anemia (only aberrant Hb is made)
Co-dominance
• Genes that exhibit more than two alternate
alleles
• ABO blood grouping is an example
• Three alleles (IA, IB, i) determine the ABO
blood type in humans
• IA and IB are codominant (both are
expressed if present), and i is recessive
Polygene Inheritance
• Depends on several different
gene pairs at different loci
acting in tandem
• Results in continuous
phenotypic variation
between two extremes
• Examples: skin color, eye
color, and height
