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Inheritance*patterns*

AD&=&autosomal&dominant&
o Characteristics:&
! affected&children&receive&disease&causing&gene&from&an&affected&parent&
! skipped&generations&NOT&common&(vertical&inheritance)&
! male&=&female&frequency&
! male&to&male&transmission&seen&
! Prognosis&worse&for&homozygote&than&heterozygote&
o Recurrent&risk&
! 50%&risk&to&the&next&offspring&regardless&of&sex&of&child&
! Affected&parent&(Aa)&+&Normal&parent&(aa):&50%&affected,&50%&normal&
! Affected&parent&(Aa)&+&Affected&parent&(Aa):&25%&homozygous&normal,&50%&
heterozygote&affected,&25%&homozygous&mutant&(LETHAL)&
AR&=&autosomal&recessive&
o Characteristics&
! Usually&only&seen&in&1&generation&of&pedigree&(horizontal&inheritance)&
! Expressed&only&in&homozygous&recessive&state&
! Parents&of&affected&children&are&obligate&carriers&
! Sibling&are&more&commonly&affected&
! Heterozygotes&do&not&normally&manifest&any&symptoms&
! Male=female&frequency&
! Consanguinity&(incest),&heterozygote&advantage,&genetic&isolation,&assertive&mating&can&
all&increase&incidence&of&AR&trait&
o Recurrent&risk&
! Carrier&(Aa)&x&Carrier&(Aa):&25%&homozygous&normal,&50%&heterozygote&normal,&25%&
homozygous&affected&(risk&of&child&being&a&carrier&is&67%&(2/3&rule)&
! Carrier&(Aa)&x&Affected&(aa):&50%&heterozygote&normal,&50%&homozygous&affected&
XD&=&X[linked&dominant&
o Characteristics&
! rarely&skips&generations&
! predominance&of&females&
! no&male&to&male&transmission&
! affected&male&transmits&to&all&daughters&
o recurrent&risk& &
! affected&father&(XaY)&+&normal&mother&(XX):&all&daughters&affected,&all&sons&are&normal&
! normal&father&(XY)&+&affected&mother&(XXa):&50%&daughters&affected,&50%&daughters&
normal;&50%&sons&affected,&50%&sons&normal&
XR&=&X[linked&recessive&
o characteristics&
! skipped&generations&
! mothers/daughters&of&affected&males&are&obligate&carriers&and&transmit&defect&to&sons&
! no&male&to&male&transmission&
! more&common&in&males&
o recurrent&risk&
! Normal&father&(XY)&+&carrier&mother&(XXa):&50%&daughters&carriers,&50%&normal;&50%&
sons&affected,&50%&normal&
! Affected&father&(XaY)&+&normal&mother&(XX):&all&daughters&obligate&carriers;&all&sons&
normal&
! Affected&father&(XaY)&+&carrier&mother&(XXa):&50%&daughters&carriers,&50%&affected;&
50%&sons&affected,&50%&normal&
Nikhil&Jain,&Keya&Patel,&Nisha&Patel&

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Mitochondrial&disease:&all&children&of&affected&female&will&have&disease;&only&affected&females&can&
transmit&disease&
Cancer&
o Inherited&Autosomal&Dominant&Cancer&Syndromes&
! associated&with&a&single&susceptibility&gene&
! actually&recessive&at&the&cellular&level,&but&with&guaranteed&loss&of&second&copy&
! 2[hit&hypothesis&
! loss&of&heterozygosity&
! usually&visualized&with&FISH&probes,&G[band&karyotype&
o Inherited&Autosomal&Recessive&Cancer&Syndromes&[&usually&defective&DNA&Repair&
! associated&with&a&single&susceptibility&gene&
! examples&include:&Xeroderma&pigmentosum;&Ataxia[telangiectasia;&Bloom&syndrome;&
Fanconi&anemia&
o familial&cancers&
! multifactorial&cause&
! Familial&clustering&of&cases,&but&role&of&inherited&predisposition&not&clear&for&each&
individual&
! Examples&include:&Breast&cancer;&ovarian&cancer;&pancreatic&cancer&
o Oncogenesis&by&Gene&Amplification&
! Double&minutes:&extrachromosomal&fragments&of&DNA&containing&an&amplified&region&of&
the&chromosome&
EGFR&is&often&amplified&as&double&minute&chromosomes&in&advanced&gliomas&&
visualized&with&FISH&probe&
Her2&is&often&amplified&as&double&minutes&in&breast&cancer&
! Homogenously&staining&regions:&Abnormal&homogeneously&staining&regions&of&
chromosomes&in&cancers&often&contain&amplified&oncogenes;&visualized&with&FISH&(gene&
amplification&in&tandem;&region&is&linked&to&chromosome)&
N[MYC&amplification&in&neuroblastomas&(NB)&
Pharmacogenetic&disorders&
o Pharmacokinetic:&Variation&in&proteins&involved&in&drug&metabolism&or&transport;&genetic&
variation&in&enzymes&that&catalyze&drug&metabolism&
o Pharmacodynamics:&Variation&in&drug&targets&or&pathways&associated&with&those&targets&
o Genetic&variation&associated&with&idiosyncratic&adverse&drug&effects&

Nikhil&Jain,&Keya&Patel,&Nisha&Patel&

Principles/definitions*
Haploinsufficiency:&loss&of&function&mutation&in&which&half&normal&lvels&of&gene&produc&result&in&
phenotypic&results&
Dominant&negative&mutation:&a&mutant&gene&product&interferes&with&function&of&normal&gene&product&
Gain&of&function:&increased&levels&of&gene&expression&or&development&of&new&function&of&gene&(novel&
property)&
loss&of&function:&mutation&that&results&in&reduced&activity&(hypomorph)&or&complete&loss&of&gene&
product&(null,&amorph)&
Hot&spot&mutation:&mutation&transmitted&from&unaffected&parent&to&affected&offspring,&but&there&is&no&
family&history&of&disease&
Pleiotropy:&affects&multiple&organ&systems&
Penetrance:&proportion&of&individuals&with&the&mutation&who&exhibit&clinical&symptoms&
o Can&be&incomplete,&age&dependent,&or&fully&penetrant&
o For&AD&disorders,&if&a&disease&expresses&penetrance,&must&take&that&into&consideration&for&
calculating&recurrent&risk&
! &new&recurrent&risk&=&(50%&chance&of&having&affected&child&x&%penetrance)/100&
Variable&expressivity:&in&individuals&who&have&inherited&the&same&mutation,&some&individuals&are&ore&
affected&than&others;&due&to&3&reasons&
o Random&chance&
o Other&genetic&factors&(modifier&loci)&
o Environmental&exposure&
Locus&heterogeneity:&mutations&of&genes&located&in&different&loci&can&produce&same&phenotype&
Allelic&heterogeneity:&different&mutations&of&same&gene&&at&same&locus&can&produce&same&phenotype&
compound&heterozygote:&affected&individual&where&there&are&2&different&inherited&genes&that&cause&
the&disorder&
pseudo[autosomal&dominance:&an&autosomal&recessive&condition&present&in&individuals&in&2&or&more&
generations&of&a&family,&thereby&appearing&to&follow&a&dominant&inheritance&pattern;&due&to:&
o high&carrier&frequency&of&disorder&
o higher&incidence&of&consanguinity&
digenic:&mutations&in&2&genes&are&additive&and&required&to&produce&the&disorder&
imprinting:&Involves&methylation&of&specific&loci&(epigenetic&change)&&&silencing&of&the&gene&
manifesting&heterozygote:&skewed&X&inactivation&(assymetric&X&inactivation)&in&which&the&number&of&
cells&that&contain&the&active&mutant&X&are&>&than&cells&that&contain&active&normal&X,&thus&carrier&female&
can&have&some&manifestations&of&the&XR&disease&&
germ&line&mutation:&mutation&that&arises&in&some&of&the&the&germ&cells&and&is&passed&to&offspring,&but&
does&not&affect&own&somatic&cells&&
heteroplasmy:&:&variable&expression&of&mitochondrial&disease&[&depends&on&how&many&mitochondria&
have&mutant&gene&&
anticipation:&triplet&repeats&are&unstable;&size&influences&severeity&and&age&of&onset&of&disease;&
expansion&occurs&primarily&during&gametogenesis&as&a&result&of&meiotic&drive&(germ&cells&containing&
expanded&repeat&show&higher&rate&of&proliferation&and&altered&expression&of&cell&cycle&regulators)&
2[hit&hypothesis&in&regards&to&cancer&
o sporadic:&mutation&occurs&in&tumor&supresors&gene&on&one&homolog&in&one&cells;&second&
mutation&occurs&in&same&gene&in&same&cell&&
o familial:&first&mutation&inherited&and&present&in&every&cells,&second&mutation&can&occur&in&any&
cell&
loss&of&heterozygosity:&affected&individual&is&heterozygous;&they&have&1&defective&allele&and&1&normal&
allele&"&2nd&hit&causes&loss&of&that&heterozygosity&and&makes&both&alleles&defective&and&homozygous&

Nikhil&Jain,&Keya&Patel,&Nisha&Patel&

!
Name!

Common!Autosomal!Dominant!Disorders!
Inheritance!
Symptoms!
Genetic!Principle!
Familial&
AD&
increased&LDL,&xanthomas&over& Haploinsufficiency&
hypercholesterolemia&&
tendons&
Marfan&
Fibrillin&
AD&
skeletal&abnormalities&(long&
Pleiotropy&and&dominant&
limbs,&pectus&excavatum),&
negative&mutations&
hypermobile&joints,&ocular&
abnormalities&(myopia,&lens&
dislocation),&cardiovascular&
disease&(mitral&valve&prolapse,&
aortic&aneurysm)&
Osteogenesis&
COL1A1&or&COL1A2& AD&
brittle&bones,&bruising,&blue&
Haploinsufficiency,&
imperfect&Type&I&
Type&I:&nonsense&
sclera;&predisposition&to&
variable&expressivity,&
(nonAdeforming)&
Type&II:&misssense&
fractures&
pleiotropy,&locus&
heterogeneity&
OI&Type&II&
perinatal&lethal;&usually&dies&
dominant&negative&
before/at&birth&
mutation,&variable&
expressivity,&pleiotropy,&
OI&Type&III&
Progressively&deforming&
OI&Tyoe&IV&
variable&phenotype,&but&normal& locus&heterogeneity&
sclera&
Neurofibromatosis& NF1&
AD&
CafAauAlait&spots,&
Allelic&heterogeneity,&high&
Type&I&
neurofibromas&(swellings&on&
penetrance,&variable&
skin),&lisch&nodules&in&iris&of&
expressivity,&pleiotropy&
eye,&bone&deformities,&learning&
disabilities&
AIP&
Cytosolic&HMG&
AD&
Change&of&normal&urine&to&dark& Haploinsufficiency&
synthase&&
purple&upon&24&hour&exposure&
(phorphobilinogen&
to&oxygen;&severe&abdominal&
deaminase)&
pain&and&colic,&agitation,&
deficiency&
tachycardia,&breathing&
problems,&nausea,&confusion,&
lower&extremity&weakness&
CharcotAMarie&
CMT&
AD,&AR,&X&
&
Locus&heterogeneity&
Tooth&
linked&&
Gene!
LDL&receptor&

Other!comments!
&
Can&also&be&caused&by&hot&spot&
mutation&

Can&also&be&caused&by&hot&spot&
mutation&

AHalf&of&cases&can&be&caused&by&
hot&spot&mutation&
ANF1&gene&codes&for&a&tumor&
suppressor&gene&
&

AD&form&caused&by&specific&
duplication&of&gene&on&
chromosome&17&

Other&AD&disroders:&Huntingtons,&Myotonic&Dystrophy,&Hypertelorism,&Holoprosencephaly,&Gorlins,&PallisterAHall,&RubensteinATaybi,&
Thanatoporic,&Achondroplasia,&Hypochondroplasia,&WAGR,&Malignant&Hyperthermia&
&
&
&

&

Nikhil&Jain,&Keya&Patel,&Nisha&Patel&

Disease!
PKU&
TayASachs&

Gene!
Phenylalanine&
hydroxylase&
deficiency&
&hexosaminidase&
A&deficiency&

Common!Autosomal!Recessive!Disorders!
Inheritance!
Symptoms!
Genetic!Principles!
AR&
Delayed&development,&low&IQ,&
Compound&heterozygosity&
mousey&odor&in&urine,&
decreased&skin&pigmentation&
AR&
NeuroAdegeneration,&clinical&
Compound&heterozygosity&
blindness,&cherry&red&spot&on&
macular,&developmental&delay&
&
AR&
Steatorrhea,&salty&sweat,&
Allelic&heterogeneity,&
respiratory&problems,&mucus&
compound&
buildup,&chronic&bacterial&
heterozygosity,&loss&of&
infections,&fat&malabsorption,&
function&
infertility&in&males&

Cystic&Fibrosis&

CFTR&&

AR&Congenital&
Deafness&

&

AR&

Deafness&

Hemochromatosis&

HFE&

AR&

Iron&overload&disorder;&delayed& Allelic&heterogeneity,&
age&of&onset;&liver&damage,&
variable&expression,&
diabetes,&bronze&skin,&cardiac&
incomplete&penetrance&
dysfunction&

Locus&heterogeneity;&
digenic&

Other!
Treated&with&Saptopterin&&A&
BH4&analog&and&tyrosine&
supplement&
&

A&Most&common&defect&is&a&class&
2&defect&causing&deletion&of&
Phe&at&codon&508&(Del&508),&
resulting&in&defective&protein&
processing&due&to&missAfolding&
!&mutant&protein&does&not&
allow&exit&from&ER&!&
ubiquination&!&lack&of&CFTR&
protein&in&plasma&membrane&
A&the&less&severe&defect&is&
R117H&(less&severe&symptoms&
due&to&less&reactive&
inflammation&response&to&
infection),&but&if&found&in&cis&
with&bad&poly&T&tract,&the&
mutation&produces&more&
severe&symptoms&
A&and&B&are&two&genetic&loci&
which&produce&proteins&
required&for&hearing&!&need&
one&big&A&and&one&big&B&to&have&
normal&hearing&
A&Even&though&it&is&AR&disease,&
symptoms&are&more&severe&in&
males&because&females&can&get&
rid&of&excess&iron&during&
menstruation&
A&most&common&mutation&is&
miss&sense&mutation&of&C282Y;&
other&mutations:&H63D&in&
which&aspartic&acid&replaced&
by&histidine&at&position&63&

Nikhil&Jain,&Keya&Patel,&Nisha&Patel&

Disease!

Gene!
ADA&deficiency&

Inheritance!
AR&

Alkaptonuria&

Homogentisate&
oxidase&deficiency&

AR&

Homocystinuria&

Cystathione&A
synthase&or&B6&
(PLP)&deficiency&&

AR&

Galactosemia&

Uridyl&transferase&
(classical)&or&
galactokinase&(non&
classical)&
deficiency&
SERPINA1&

AR&

Dnmt3b&

AR&

SCID&

A1AT&(1&
antitrypsin)&

ICF&&

AR&

Symptoms!
Build&up&of&dATP&is&toxic&to&B&
and&T&cell&development&
Delayed&age&of&onset;&arthritis,&
discoloration&of&cartilage&and&
CT&(ocronosis),&darkening&of&
urine,&bluish&sclera&&&auriculum&
Discoloration&of&lens,&skeletal&
abnormalities,&osteoporosis,&
premature&arterial&disease,&
mental&retardation,&
atherosclerosis&
Classical:&Liver&failure,&jaundice,&
hepatomegaly,&cataract,&
hypoglycemia&on&galactose&
ingestion&
Non&classical:&cataracts&
Gene&defect&leads&to&deficiency&
of&&1&antitrypsin&!&cannot&
counteract&neutrophil&elastase&
activity&!&destruction&of&alveoli&
causing&lung&disease,&COPD,&
emphysema;&liver&disease&is&
associated&with&those&who&have&
PiZZ&genotype&(forms&
aggregates/polymers&in&
hepatocytes)&

Genetic!Principles!
Locus&heterogeneity&

Other!
&

&

&

&

Treated&with&cofactor&
supplement&

&

&

Loss&of&function&(w/o&&
1AT,&elastase&destroys&
alveoli),&gain&of&function&
(abnormal&&1AT&can&
accumulate&in&liver&!&
cirrhosis;&associated&with&
PiZZ),&codominance&

Facial&dysmorphism,&mental&
retardation,&prolonged&and&
recurrent&infections,&immune&
deficiency,&decreased&IgA&

&

A&Smoking&is&a&major&risk&factor&
!&Oxidation&of&methionine&in&
the&active&site&of&&1AT&!&
reduces&affinity&of&&1At&for&
elastase&
A&3&alleles&of&SERPINA1&
&1.&PiM:&most&common&allele&in&
normal&population&
&2&PiZ:&most&common&
deficiency&allele&constituting&
95%&of&cases&(glutamate&
substituted&by&lysine&at&
position&342)&
&3.&PiS:&only&of&concern&when&it&
decreased&concentration&of&
A1AT&to&less&than&40%&
immunodeficiency&centromeric&
instability&facial&anomalies&
syndrome&

Other&AR&disroders:&Freidrich&Ataxia,&Blooms,&Fanconi&Anemia,&Xeroderma,&Ataxia,&Sickle&Cell&+&all&isoforms,&alpha&thalassemia,&beta&
thalassemia,&Butyrylcholinesterase&deficiency,&NATA2&deficiency,&CYP2D6&polymorphism,&TMTP&polymorphism&
&
&

&

Nikhil&Jain,&Keya&Patel,&Nisha&Patel&

!
Disease!

DMD&

Beckers&
XALinked&SCIDS&
&
GlucoseA6A
Phosphate&
Dehydrogenase&
(G6PD)&Deficiency&&
&

Lesch&Nyhan&

RedAGreen&color&
blindness&
Rett&Syndrome&

Gene!
Dystrophin&

Inheritance!
XR&

milder&mutation&of&
dystrophin&
SCIDX1:&defect&in&
gamma&chain&of&
receptor&for&IL2RG&
G6PD&deficiency&
&

XR&
XR&
&
XR&

Hypoxanthine&
XR&
Guanine&
Phosphoribosyl&
Transferase&
(HGPRT)&deficiency&
&
XR&

Mutation&of&X&
linked&MeCP2&gene&

XD&

Sex!Linked!
Symptoms!
enlarged&calves,&wasting&of&
thigh&muscles,&difficulty&
standing&and&walking,&Gower's&
maneuver;&onset&2A6&y/o;&lethal&
before&age&of&30&
&
Later&onset&and&milder&
symptoms&
T&cells&lacking&receptor&cannot&
mature,&lacking&mature&B&cells&
!&same&as&autosomal&SCIDS&
hemolytic&anemia&on&ingestion&
of&sulfa,&primaquines,&fava&
beans,&or&antimalarial&drugs&!&
lots&of&oxidative&stress&most&
common&form&of&hemolytic&
anemia;&reduces&amount&of&
NADPH&available&to&reduce&GSH&
in&RBC;&also&leads&to&Heinz&
bodies&
hyperuricemia,&gout,&self&
mutilation,&involuntary&
movements,&orange&crystals&
found&in&diaper&
non&lethal;&redAgreen&color&
blindness&
&

Genetic!Principles!
may&manifest&in&females&
due&to&"manifesting&
heterozygote"&
phenomenon:&causes&
symptoms&such&as&
muscular&weakness&and&
elevated&creaitne&kinase&
&

Other!
A&low&genetic/reproductive&
fitness&
A&defect&caused&by&frameshift&
mutation&but&also&can&arise&
from&hot&spot&mutation&

locus&heterogeneity&
&
&
&

IL2RG&=&interleukin&gamma&c&
cytokine&receptor&

&

&

&

A&males&are&homozygous&
A&homozygous&color&blind&
females&are&rare&

&

&

males&with&the&mutant&X&gene&
variable&expressivity&due&
die&in&utero/soon&after&birth;&
to&skewed&X&inactivation&&
Children&develop&normally&until& &
6&to&18&months;&Regression&
phases:&loss&of&speech,&acquired&
hand&skills;&most&develop&
seizures,&repetitive&hand&
movements,&irregular&breathing&
and&motor&control&problems.&&

A&methylAcytosine&binding&
protein&2&(MeCP2)&recruits&
HDAC&
A&Disorder&maybe&due&to&
germline&mutation/mosaic&&
A&95%&cases&are&not&inherited&
and&there&is&no&family&history&
!&they&are&caused&by&new&
mutations&in&the&MECP2&gene&&
&

Nikhil&Jain,&Keya&Patel,&Nisha&Patel&

Disease!
Incontinentia&
Pigmenti&

Gene!
mutation&of&the&XA
linked&IKBKG&gene&

Inheritance!
XD&

Symptoms!
males&w/&disorder&die&in&utero;&
females&less&severalty&affected,&
but&can&manifest&as&blisters&and&
rashes&early&in&life;&later&in&life&
there&are&patches&of&
hyperpigmentation&in&areas&
where&normal&X&is&inactive&and&
mutant&X&is&active&(Marble&
Cake),&mental&retardation,&and&
retinal&detachment&

Genetic!Principles!
variable&expressivity&due&
to&skewed&X&inactivation&

Other!

Vit.&D&Resistant&
Rickets&
hypophosphatemic&
Y&linked&disorders&

&

XD&

Bone&demineralization,&bow&leg,& &
rachitic&rosary,&pigeon&chest&

resistance&to&vitamin&D&AA>&
decreased&calcium&absorption&

&

Y&linked&

&

&

Leber&Hereditary&
Opti&Neuropathy&

MTND&

Mitochondrial&

Progressive&blindness&
around&20A30&years&

heteroplasmy&
&

SRY&gene&defect&
hairy&ears&
H&Y&histocompatibility&antigen&
&

MELAS&

MTND,&MTTL,&
MTTV,&MTTH&

Mitochondrial&

Heteroplasmy,&locus&
heterogeneity&

&

MERRF&
&

MTTK&

Mitochondrial&

Heteroplasmy&

&

Retinitis&
Pigmentosa&

ROM1&and&
peripherin&

&

mitochondrial&encwphalopathy,&
lactic&acidoses,&stroke&like&
episodes&
myoclonic&epilepsy&with&ragged&
red&muscle&fibers&
&
progressive&visual&impairment,&
rods&are&degenerating&

digenic&

must&have&genotype&AaBb&to&
show&phenotype&
&
&
&

&

Other&X&linked&disorders:&Fragile&X&Syndrome,&Hemophilia&A/B&
&
&
&

Nikhil&Jain,&Keya&Patel,&Nisha&Patel&

Disease!
Turner&syndrome&

Gene!
45,&X&patient&
(absence&of&barr&
body)&
&

Inheritance!
Meiosis&non&
disjunction&&
&

Klinefelter&
syndrome&

47,&XXY&patient&

Meiosis&non&
disjunction&&

Down&syndrome&

trisomy&21&

Meiosis&1&non&
disjunction/&
Robertsonian&
translocation&
between&
chromosome&
21&+&14&

Patau&Syndrome&

Trisomy&13&

Non&
disjunction&
during&
oogenesis&

Edwards&Syndrome&& Trisomy&18&

Non&
disjunction&
during&
oogenesis&

&
&

Chromosomal!Aneuploidies!
Symptoms!
short&stature,&swelling,&broad&
chest,&low&hairline,&lowAset&ears,&
and&webbed&necks;&gonadal&
dysfunction&amenorrhea&
(absence&of&menstrual&cycle),&
sterility,&visual/spatial&
disabilities;&coarctation&of&
aorta,&skin&folds&prominent,&
stunted&growth,&good&
prognosis,&but&unable&to&
reproduce;&some&learning&
disabilities&like&poor&spatial&
cognition;&cystic&hygroma&A&
abnormal&formation&of&
lymphatics&and&fluid&build&up&
testicular&atrophy,&
gynecomastia,&female&
distribution&of&hair,&infertility&

Genetic!Principles!
haploinsufficiency&of&
genes&on&petite&arm&that&
causes&X&inactivation&
gives&rise&to&phenotype&

Other!
A&Meiosis&I&nondisjunction&A&
child&does&not&receive&X&from&
father&in&most&cases&
A&many&are&mosaics;&some&have&
isochromosome&of&one&of&the&X&
chromosomes&A&they&only&have&
1&component&of&the&short&arm&
of&X&chromosome&and&the&
isochromosome&is&usually&
inactivated&

&

Caused&by&meiosis&I&
nondisjunction&in&dad&or&
meiosis&I&or&II&nondisjunction&
in&mom&
Increased&maternal&age&is&risk&
factor&

mental&impairment,&stunted&
&
growth,&flat&head,&slanted&eyes,&
flattened&nose,&congenital&heart&
defects;&develop&changes&
similar&to&Alzheimers&at&young&
age&(amyloid&protein&for&
Alzheimers&located&on&
chromosome&21)&&
polydactyly,&cleft&lip&and&palate,& &
microphthalmia,&microcephaly,&
intellectual&disability&(only&have&
1&hemisphere),&cardiac&and&
kidney&anomalies&
clenched&fist,&overlapping&of&
&
fingers,&rocker&bottom&feet,&
congenital&heart&defects,&
microcephaly,&intellectual&
disability,&small&lower&jaw;&poor&
prognosis&

&

&

&
Nikhil&Jain,&Keya&Patel,&Nisha&Patel&

!
Inheritance!

Disease!
CriAduAchat&

Gene!
Deletion&of&
chromosome&5p&

DiGeorge&
(Velocardiofacial)&

Microdeletion&of&
chromosome&22q&

&

WolfAHirschhorn&

Deletion&of&
chromosome&4p&

&

WAGR&

Microdeletions&of&
PAX6&locus&
chromosome&11&&
WT1&Gene&
Deletion&of&
maternal&
chromosome&
15q11&resulting&in&
missing&maternal&
UBE3A&
Deletion&of&
paternal&
chromosome&
15q11&resulting&in&
missing&paternal&
SNERPN&
Missing&maternal&
11p15&

&

Angelman&

Prader&Willi&

BeckwithA
Wieddmann&

&
&

&

Microdeletio
n&of&UBE3A&
or&paternal&
uniparental&
disomy&

Microdeletions!
Symptoms!
high&pitched&cat&like&cry,&severe&
intellectual&and&speech&
disability,&microcephaly&
Congenital&heart&defects,&
absence&of&thymus,&cleft&
lip/palate,&learning&disabilities,&
speech&difficulty,&narrow&
palpebral&fissure,&prominent&
nasal&root,&increased&risk&for&
schizophrenia&
Facial&anomalies&wide&spaced&
eyes,&prominent&nose,&abnormal&
iris,&cardiac&anomalies,&
intellectual&and&developmental&
delay&
Wilms&tumor,&aniridia,&
genitourinary&malformations,&
retardation&of&growth&and&
development&
Happy&puppet,&happy&
disposition,&severe&mental&
retardation,&puppet&like&
posture,&seizures&

Genetic!Principles!
&
&

Other!
FISH&and&array&CGH&are&
diagnostic&
&
FISH&and&array&CGH&are&
diagnostic&
&

&

&

&

&

Imprinting&

Increased&risk&in&IVF&children&

Microdeleito
n&of&SNERPN&
or&maternal&
uniparental&
disomy&

Hypotonia&in&infancy,&failure&to& Imprinting&
thrive,&if&they&do&thrive&&obese,&
mental&and&developmental&
delay,&underdeveloped&genitalia&

Detected&by&FISH&and&
methylation&analysis&via&
Southern&Blot&

Sporadic&
maternal&
chromosomal&
rearrangeme
nt&or&paternal&
uniparental&
disomy&

Macroglossia,&birth&weight&and&
length&greater&than&90th&
percentile,&abdominal&wall&
defects&like&umbilical&hernia,&
ear&creases/pits,&neonatal&
hypoglycemia,&increased&risk&of&
cancer&

Children&of&IVF&have&4A9&fold&
higher&risk&of&developing&
disease&because&it&causes&
abnormal&methylation&&

Imprinting&

&
Nikhil&Jain,&Keya&Patel,&Nisha&Patel&

!
Disease!
Huntington&

Gene!
Inheritance!
CAG&expansion&of&
AD&
exon&1&@&5'&protein&
coding&region&of&
Huntingon&gene&AA>&
polyglutamine&tract&
within&Huntington&
protein&&

Myotonic&Dystropy&

CTG&expansion&@&
3'&UTR&of&DMPK&
gene&
&

Friedreich&Ataxia&

GAA&expansion&in&
AR&
intron&1&of&frataxin&
gene&AA>&formation&
of&heterochromatin&
AA>&transcriptional&
repression&of&
frataxin&gene&&
&

AD&

Triplet!Repeats!
!
Symptoms!
Genetic!Principles!
Other!
movement&abnormality,&
paternal&anticipation;&gain& A&incidence:&3A7/100,000&
emotional&disturbance,&
of&function&mutation&
(European)&
cognitive&impairment&death&10A &
A&mean&age&of&onset&40y/o;&
15&years&after&onset/late&onset;&
increase&in&polyglutamne&tract&
neurodegenerative&A&
length&causes&protein&to&
progressive&
aggregate&and&form&inclusion&
dementia/involuntary&
bodies&that&are&toxic&
movements;&cerebral&cortex&
A&abnormal&protein&also&
degeneration;&chorea&caused&by&
interacts&with&different&
basal&ganglia&degeneration,&
transcription&factor&proteins&
cognitive&and&language&decline&
that&causes&dysregulation&of&
gene&expression&
muscle&loss,&weakness&of&face&
maternal&anticipation:&
A&repeat&soaks&up&RNA&binding&
and&jaw&muscles,&eye&drooping,& Most&pleiotropic&
proteins&leading&to&global&
cardiac&arrhythmia/heart&
phenotype&of&all&unstable& changes&in&RNA&processing&AA>&
effects,&testicular&atrophy,&
triplet&repeat&disorders;&
altered&cell&function&and&
frontal&baldness,&cataracts;&
gain&of&function&&
splicing&alterations&
muscle&wasting&especially&in&
&
A&&incidence&1/8000&
distal&muscles;&insulin&
&
resistance;&developmental&and&
learning&delay;&speech&and&
language&affected&
Early&onset&&seen&between&5&to& paternal&anticipation;&loss& A&repeat&expansion&alters&
15&yrs&&with&progressive&gait&
of&function&
chromatin&structure&involving&
and&limb&ataxia;&areflexia&in&all&
formation&of&triplex&DNA&and&
4&limbs;&hypertrophic&
DNA&methylation&of&bases&and&
cardiomyopathy;&axonal&
histone&methylation&
sensory&neuropathy;&
A&incidence:&1/50000&
kyphoscoliosis;&first&symptoms&
A&carrier&frequency&1/110&
are&loss&of&tendon&reflexes&in&
A&expansion&of&200&to&>900&can&
ankles&and&knees&and&trouble&
cause&disease&
walking.&Progressive&
&
neurodegenerative&disease.&
muscle&weakness,&vision&and&
hearing&impairment;&usually&die&
of&heart&disease.&Lack&of&muscle&
coordination&during&voluntary&
movements;&late&onset&between&
20A35&yrs.&

Nikhil&Jain,&Keya&Patel,&Nisha&Patel&

Disease!
Fragile&X/Martin&
Bell&

Gene!
Inheritance!
CGG&expansion&@&
XD&
5&UTR&in&promoter&
of&FMR1&gene&!&
methylation/&gene&
silencing&!&FMR1&
protein&is&absent&
&

Spinocerebellar&
Ataxia&1,&2,&3,&6&

CAG&expansion&in&
exon&
&

AD,&AR,&X&
linked&
&

Spinocerebellar&
Ataxia&8&
&

CTG&expansion&@&
3&terminal&exon&of&
a&non&protein&
coding&RNA&in&the&
SCA8&gene&

&

&
&
&

Symptoms!
mental&retardation,&
cluttered/nervous&speech,&
prominent/large&ears&and&jaw,&
large&eyes&that&stick&out,&post&
pubertal&macroAorchidism&
(enlarged&testis)&in&males,&low&
muscle&tone&and&flat&feet;&ADD&
in&females&
progressive,&muscle&
degenerative&disease&
&
progressive,&muscle&
degenerative&disease&
&

Genetic!Principles!
exclusively&maternal&
anticipation;&loss&of&
function&(methylation&!&
silencing)&

paternal&anticipation&with&
variable&expression&and&
variable&age&of&onset;&
locus&heterogeneity;&
variable&life&span&
&

Other!
A&repeat&expansion&causes&
fragile&site&observed&on&
standard&karyotype&
A&5A50&repeats&normal&
A&50A200&repeats&9ermutation;&
A&>200&repeats&is&full&mutation&
&
most&are&causes&by&CAG&repeat&
polylgutamine&disorder&that&
can&affect&protein&function,&
interaction,&aggregation,&and&
toxicity&
repeat&expansion&alters&
protein&binding&to&RNA&
&

&

Nikhil&Jain,&Keya&Patel,&Nisha&Patel&

Disease!
Bloom&Syndrome&

Gene!
BLM&gene&for&DNA&
Helicase&

Inheritance!
AR&cancer&

Fanconi&Anemia&

Fanc&AAH&gene&

AR&cancer&

Xeroderma&
Pigmentosum&

NER&

AR&cancer&

Ataxia&
telangiectasia&

&ATM&

AR&cancer&

Familial&
Breast/Ovarian&
Cancer&

BRCA1/BRCA2&

Hereditary&
nonpolyposis&colon&
cancer&(Lynch&
Syndrome)&

&
&

Familial&
multifactorial&
(but&does&
follow&AD&
cancer&
pattern:&1st&
hit&inherited,&
2nd&hit&is&
somatic)&
MSH2,&MLH1&(Code& Familial&AD:&
for&miss&match&
1st&hit&
repair&genes)&
inherited,&2nd&
hit&somatic&

DNA!Repair!Defects!
Symptoms!
Genetic!Principles!
Smaller&than&average,&narrow&
&
chin,&prominent&nose&and&ears,&
facial&rash&upon&exposure&to&
sun,&gets&diabetes,&neurological,&
lung&and&immune&deficiencies&
Radial&ray&defect,&pancytopenia,& Locus&heterogeneity&
mental&developmental&
problems,&short&stature&

Other!
Chromosomal&instability:&
chromosomal&breaks&and&sister&
chromatid&exchanges&!&higher&
risk&of&cancers&

Increased&spontaneous&
chromosome&breakage&!&
worse&by&exposure&to&DNA&
cross&linking&agents&
Variable&expression,&locus& DNA&damage&is&cumulative&and&
heterogeneity&&
irreversible&!&1000&fold&
increase&of&risk&for&skin&cancer&

Extreme&sun&sensitivity,&sun&
burns/blistering,&freckled&with&
hyper&pigmented&skin&lesions,&
ocular&involvement&
(conjunctivitis&+&ocular&
tumors),&progressive&
neurological&degeneration&
Affects&cerebellum&(ataxia),&and& &
immune&system;&increased&risk&
of&cancer;&ocular&telangiectasia&&
Incidence&1/12&in&western&
society,&1/3&affected&women&go&
on&to&develop&aggressive&
tumors,&up&to&20%&have&familial&
history,&pancreatic&and&other&
cancers&also&more&common,&
male&breast&and&prostate&cancer&
incidence&also&increased&

Loss&of&function&(when&
BRCA&is&lost,&cell&can&
duplicate&with&DNA&
damage&and&turn&into&
cancer),&allelic&
heterogeneity&

few&polyps,&progresses&rapidly;& Locus&heterogeneity&
Tumors&also&exhibit&
microsatellite&instability.&(Short&
repetitive&sequences&of&DNA)&

ATM&is&a&serine&threonine&
kinase&involved&in&detecting&
DNA&damage&and&activating&
cell&cycle&arrest&and&DNA&
repair&proteins&(p53)&
A&Also&classified&as&DNA&repair&
defect:&genes&are&involved&in&
DNA&repair&and&apoptosis&
when&DNA&cant&be&repaired&
A&lifetime&penetrance&about&
85%&for&breast&and&55%&
(BRCA1)&or&25%&(BRCA2)&for&
ovarian&cancer&
A&Microsatellite&instability&
(simple&repetitive&DNA&
sequences)&
A&Also&classified&as&DNA&repair&
defect&

&

Nikhil&Jain,&Keya&Patel,&Nisha&Patel&

Blood!Disorders!
Symptoms!
Tissue&hypoxia,&ischemic&pain,&
sickling&of&RBC&

Disease!
Sickle&Cell&

Gene!
&&globn&chain&
gene&of&Hb&

Inheritance!
AR&

Genetic!Principles!
PseudoAautosomal&
dominance,&compound&
heterozygosity&
PseudoAautosomal&
dominance,&compound&
heterozygosity&

Hemoglobin&S&&
Sickle&Cell&

&A&globin&gene&

AR&

Individuals&suffer&sickle&cell&
crisis&episodes;&there&are&NO&
manifestations&of&sickle&cell&
anemia&during&fetal&life&because&
of&predominance&of&HbF.&crises&
caused&by&anemia,&hemolysis,&
vasoAocclusive&ischemia&around&
abdomen&and&long&bones.&
&

Hemoglobin&AS&

&globin&gene&

AR&

produce&both&normal&and&
abnormal&hemoglobin,&
generally&regarded&as&benign&
condition.&can&develop&clinical&
problems&of&sickle&cell&crisis&in&
low&oxygen&saturation&(deep&
sea&diving&and&unpressurized&
aircraft,&extreme&exercise)&

Hemoglobin&C&

&&globin&gene&

AR&

people&who&are&homozygous&for& &
HbC&have&mild&hemolysis;&HbC&
has&lower&solubility&than&HbA&
and&tends&to&crystallize&in&RBCs&

Hemoglobin&SC&

&&globin&gene&

AR&

may&have&similar&episodes&of&as&& &
sickle&cell&disease&

&

Other!
Defect&due&to&single&BP&
mutation&in&which&glutamate&is&
replaced&by&valine&at&position&6&
A&Defect&due&to&single&BP&
mutation&in&which&glutamate&is&
replaced&by&valine&at&position&6&
(point&mutation,&transversion,&
missense)&
A&can&use&hemoglobin&
electrophoresis,&ASO,&or&RFLP&
for&diagostic&tests&
A&HbS&moves&slower&to&anode&
than&HbA&in&hemoglobin&
electrophoresis&
A&TREATMENT&A&drugs&that&
increase&expression&of&fetal&
hemoglobins:&5Aazacytidine&
(Decitabine),&hydroxyurea,&
butyrate&compound&
A&heterozygous&carrier&=&sickle&
cell&trait;&1&normal&&Aglobin&
gene,&1&HbS&gene&
A&in&parts&of&Africa,&the&
Mediterranean&basin,&the&
Middle&East&and&India,&a&deadly&
form&of&malaria&(falciparum&
malaria)&very&common&A&people&
who&inherited&one&HbS&gene&
(heterozygotes)&had&a&survival&
(heterozygote)&advantage&AA>&
explains&high&rate&of&carriers&in&
these&areas&
A&missense&point&mutation&at&
position&6&of&the&&&Aglobin&
gene&(glutamic&acid&AA>&lysine)&
A&HbC&moves&slowest&to&anode&
on&Hb&electrophoresis&
two&different&mutations&of&&&&
globin&gene&(HbS&and&HbC)&

Nikhil&Jain,&Keya&Patel,&Nisha&Patel&

Disease!
&thalassemia&

Gene!
&globin&gene&
cluster&on&
chromosome&16&

Inheritance!
AR&
&

Symptoms!
A&Frontal&bossing,&malar&
prominence&&indicative&of&
extramedullary&hematopoiesis&
A&Loss&of&one&gene&(/&A)&is&a&
silent&carrier&with&no&clinical&
problems&
ALoss&of&two&genes&in&trans&(A/&
A)&or&cis&(/A&A)&is&a&carrier&
and&results&in&mild&anemia&&(cis&
worse&than&trans)&

Bart&Syndrome&
Hydrops&Fetalis&
&

&globin&

AR&

HbH&disease&

&gene&

AR&

&&thalassemia&

HBB&&&globin&gene& AR&
on&chromosome&11&

The&most&severe&form;&
&
characterized&by&fetal&onset&of&
generalized&edema,&ascites,&
pleural&and&pericardial&
effusions,&and&severe&
hypochromic&anemia;&Death&in&
the&neonatal&period&is&almost&
inevitable.&
infant&or&child&with&a&mildAtoA
&
moderate&(rarely&severe)&
microcytic&hypochromic&
hemolytic&anemia&and&
hepatosplenomegaly;&Mild&
thalassemiaAlike&bone&changes&
are&present&in&approximately&
oneAthird&of&affected&
individuals;&is&compatible&with&
survival&into&adulthood&
Excessive&&Aglobin&chains&
&
precipitate&!&severe&hemolytic&
anemia;&Bone&marrow&
compensates/expands&to&
perform&erythropoiesis&!&bone&
deformity/fractures;&Mutations&
(o)&prevent&any&formation&of&&
chains;&Mutations&(+)&allow&
some&&chain&formation&to&
occur&

&

Genetic!Principles!
&

Other!
A&&Athalassemia&is&most&
commonly&a&result&of&gene&
deletions&(&globin&gene&
deletion&can&be&caused&by&
unequal&crossing&over&during&
homologous&recombination)&
A&there&are&2&Aglobin&genes:&1&
and&2&(an&individual&has&4&
copies&of&Aglobin&genes)&&
A&common&in&SE&Asia,&Africa,&
and&the&Mediterranean.&&
A&Loss&of&all&4&Aglobin&genes&is&
lethal&(A&A/A&A)&
A&aggregation&of&gammaA4&
tetramers&(as&there&is&
deficiency&of&aAglobin&chains)&
&
&
A&Loss&of&three&genes&(&A/A&A)&
cause&&&4&tetramers&referred&
to&as&HbH,&which&causes&
moderate&hemolytic&anemia&
A&there&is&deficiency&of&Aglobin&
chains&

&

&
Nikhil&Jain,&Keya&Patel,&Nisha&Patel&

Disease!
&thalassemia&
major/Cooley's&
Anemia/&
Mediterranean&
Anemia&

Gene!
Inheritance!
HBB&&&globin&gene& AR&
on&chromosome&11&

Symptoms!
A&homozygotes&or&compound&
&
0
heterozygotes&for& &or&+&
genes&&two&severe&mutations&&
A&Very&low&or&absent&HbA&levels;&
High&HbA2&and&HbF&levels&
A&&present&at&about&six&months&
as&Aglobin&genes&are&switched&
off&

&thalassemia&
intermedia&

HBB&&&globin&gene& AR&
on&chromosome&11&

&

&thalassemia&
HBB&&globin&gene& AR&
minor/&carrier/&
on&chromosome&11&
trait/&heterozygous&

No&significant&clinical&
manifestations&

Hemophilia&B&

Factor&IX&deficiency& XR&

Hemophilia&A&

factor&VIII&
deficiency&

Carrier&females&are&generally&
asymptomatic,&however,&in&
some&carrier&females&a&lower&
level&of&clotting&factors&is&seen,&
and&manifestations&resemble&
affected&males&
A&increased&tendency&to&bleed&
after&minor&trauma,&easy&
bruising,&spontaneous&
hemorrhage&into&joints&and&
muscles,&easy&bruising,&and&
prolonged&bleeding&from&
wounds.&
A&Carrier&females&generally&
asymptomatic,&but&in&some&
carrier&lower&level&of&clotting&
factors&is&seen,&and&
manifestations&resemble&
affected&males&

XR&

Genetic!Principles!

Other!
Regular&transfusions&correct&
the&anemia&and&suppress&
erythropoiesis,&but&lead&to&iron&
deposition.&Iron&chelation&and&
dietary&control&can&manage&
these&complications;&definitive&
cure&is&bone&marrow&
transplantation&from&an&HLAA
identical&sibling.&
&
A&mostly&homozygotes&or&
compound&heterozygotes&
(different&+&mutations&on&the&&
&Aglobin&genes)&&one&severe&
mutation,&second&mutation&is&
less&severe&
A&Low&HbA&levels&&as&there&is&
some&&globin&synthesis&
&
A&mostly&heterozygotes&(one&
normal&and&one&mutant&&A
globin&gene)&
A&Almost&normal&HbA&levels&
Allelic&heterogeneity&
Point&mutations&and&deletions&
A&can&result&in&females&due& in&the&Factor&IX&gene&are&the&
to&manifesting&
most&common&causes&of&
heterozygote&&skewed&X& hemophilia&B&
inactivation&
allelic&heterogeneity&
&
can&result&in&females&due&
to&manifesting&
heterozygote&&skewed&X&
inactivation&(leading&to&a&
higher&percentage&of&
inactivation&of&the&normal&
XAchromosome)&

A&deficiency/mutation&of&
clotting&due&to&large&inversion&
(40%),&or&deletion,&insertion,&
point&mutation&(50A60%);&The&
gene&for&Factor&VIII&(F8C)&is&
unusually&large&&
A&can&also&be&caused&by&germ&
line&mutation&(mosaicism)&or&
hot&spot&mutation&

&

Nikhil&Jain,&Keya&Patel,&Nisha&Patel&

Disease!
Hypertelorism&
Holoprosenchephaly&

Gene!
Shh&(sonic&
hedgehog)&
Shh&or&Six3&
(regulator&of&Shh)&

Inheritance!
AD&
AD&

SmithALemiAOpitz&
Syndrome&(SLOS)&

7Adehydrocholesterol& AR&
reductase&deficiency&

Gorlin&
Syndrome/Nevoid&
basal&cell&
carcinoma&
PallisterAHall&
Syndrome&

Patched&(Ptch)&A&
receptor&for&Shh&

AD&

Gli&genes&
&

RubensteinATaybi&
Syndrome&&
Polydactyly&

Thanatophoric&
Dysplasia&

Developmental!Disorders!
Symptoms!
mediolateral&expansion&of&face&
and&ventral&forebrain&
facial&abnormalities,&mild&
hypotelorism,&single&central&
maxillary&incisor,&
micerocephaly,&cleft&palate/lip,&
cyclopia&

Genetic!Principles!
&
Variable&expressivity&

microcephaly,&mental&
retardation,&malformation&of&
mesodermal&origin,&syndactly,&
polydactyly&
rib&defects,&early&age&basal&cell&
carcinoma&

Variable&expressivity&

AD&

brain&tumors,&polydactyly&

&

CREBBP&gene&

AD&

broad&thumbs&and&toes,&mental&
disability,&short&stature,&small&
head,&facial&features&

&

ectopic&
expression/over&
expression&of&Shh,&
mutation&in&Gli3&in&
limb&bud,&OR&
disruption&of&
Hoxd13&
extracellular&
domain&and&distal&
tyrosine&kinase&
domain&of&FGFR3A&

&

more&than&normal&number&of&
fingers&or&toes&
&

&

AD&

similar&to&homozygous&
allelic&heterogeneity&
achondroplasia&A&lethal;&short&
&
limbs,&narrow&chest,&small&ribs,&
undeveloped&lungs,&enlarged&
head;&usually&still&born&
appear&normal&at&birth,&but&as&
Allelic&heterogeneity&
child&grows,&arms&and&legs&do&
not&develop&properly&and&
proportionally;&normal&life&span&

Hypochondroplasia& Defect&in&proximal&
and&distal&tyrosine&
kinase&domain&of&
FGFR3&

AD&

&

Other!
Due&to&increasing&Shh&in&the&
frontal&nasal&prominence&&
A&Heterozygous&mutations&of&
SHH&result&in&one&form&of&
autosomal&dominant&
holoprosencephaly&(HPE3)&&
A&incidence&=&1/5,000&A&
1/10,000&live&births&
incidence&=&1/20,000A
1/40,000&
&
A&Usually&caused&by&new&hot&
spot&mutation&
A&incidence&=&1/56,000A
1/164,000&
A&Usually&caused&by&new&hot&
spot&mutation&
A&extremely&rare&
A&Usually&caused&by&new&hot&
spot&mutation&
A&incidence&=&1/125,000&
&

&

&

Nikhil&Jain,&Keya&Patel,&Nisha&Patel&

Disease!
Achondroplasia&

Gene!
FGFR3&(fibroblast&
growth&factor&
receptor&3)&&

Inheritance!
AD&

Symptoms!
short&limbs,&normal&torso,&
reduced&height,&large&head,&flat&
nose&at&bridge,&short&stubby&
fingers,&trident&hand,&normal&
life&expectancy;&&homozygote&is&
lethal&

Genetic!Principles!
full&penetrance;&gain&of&
function&(decrease&in&
chondrocyte&
differentiation&and&
formation&of&osteoblast);&
allelic&heterogeneity&

de&la&Chapelle&(46,&
XX&Male)&

translocation&of&
SRY&gene&on&Y&
chromosome&&

unequal&
crossing&over&
during&
meiosis&

46,&XY&Swyer&
Syndrome&(Pure&
Gonadal&
Dysgenesis)&
&

mutation&of&SRY&
gene&s&coding&
sequence&or&
regulatory&
sequence&

&

typical&boys/men,&slightly&
&
shorter&than&normal&stature,&
normal&external&genitalia,&10%&
w/&hypospadia,&mullerian&
tissue&absent&(normal),&
infertility&(azzospermia&factors&
do&not&translocate&along&with&
SRY&gene)&
normal&female&genitalia,&well&
loss&of&function&
developed&mullerian&strucure&
&
(normal),&bilateral&streak&
gonads&instead&of&ovaries&or&
testis;&delayed&onset&of&puberty,&
elevated&LH&causes&
clitoromegaly&

Other!
A&Mutation&is&due&to&GAC&
transversion&resulting&in&
arginine&AA>&glycine&at&position&
360&and&is&located&at&
transmembrane&domain&at&CpG&
site&
A&mutation&of&FGFR3&AA>&
chondrocyte&growth&AA>&
prevents&differentiation&to&
bone&at&growth&plate&
A&Can&also&be&caused&by&hot&
spot&mutation&
A&FGFR3&gene&codes&for&
transmembrane&receptor&that&
is&involved&in&differentiation&of&
cartilage&to&bone&
A&80%&due&to&spontaneous&
mutation&in&spermatogenesis&
(increased&paternal&age&is&risk&
factor)&
A20%&due&to&inheriting&
mutation&from&one&parent;&&
A&incidence&=&1/10,000A
1/40,000&
incidence&=&1/20,000&
&

A&Usually&due&to&new&mutation&
A&increased&risk&of&germ&line&
tumors&
A&treatment:&remove&streak&
gonads&and&hormone&
replacement&with&estrogen&and&
progesterone&
A&incidence&=&1/80,000&

Nikhil&Jain,&Keya&Patel,&Nisha&Patel&

! Cancers!
Symptoms!
lymphocytes&fail&to&differentiate&
(undergo&rapid&cell&divisions)&=&
cancer&
&

Disease!
Burkitt&Lymphoma&

Gene!
MYC&oncogene&on&
chromosome&8&
fuses&to&
immunoglobulin&
locus&on&
chromosome&14&
t(8;14)(q24;q32)&

Inheritance!
Somatic&
mutation&

Genetic!Principles!
oncogenic&activation&by&
translocations&(aka&
illegitimate&
recombination)&

Chronic&Myeloid&
Leukemia&(CML)&

BCRAABL&
translocations&
resulting&in&
Philadelphia&
Chromosome&
t(9;22)(q34;q11);&&
&

&

Usually&asymptomatic,&but&
some&present&with&
hepatosplenomegaly&and&
associated&abdominal&pain&

Wilms&tumor&

WT1&gene&on&
Chromosome&11&

AD&

an&abnormally&large&abdomen,&
loss&of&function,&twoAhit&
abdominal&pain,&fever,&nausea&
hypothesis,&loss&of&
and&vomiting,&blood&in&the&urine& heterozygosity&
&

WAGR&

WT1&gene&

AD&

Retinoblastoma&
(childhood&cancer)&

Rb&gene&on&
chromosome&13&&

Sporadic&2&
somatic&
mutations&
&
Familial&AD&
1st&hit&
inherited,&2nd&
hit&somatic&

Wilms&tumor,&aniridia,&
genitourinary&malformations,&
retardation&of&growth&
Sporadic:&single&tumor,&
unilateral,&late&onset&
&
Familial:&multiple&tumors,&
bilateral,&early&onset&

&

&
loss&of&function,&twoAhit&
hypothesis,&loss&of&
heterozygosity&

Other!
A&MYC&is&a&nuclear&
transcription&factor&important&
for&G1/S&transition&that&
stimulates&the&cell&cycle&
A&level&of&MYC&oncogene&
expression&is&increased&as&MYC&
is&now&under&regulation&of&IgH&
promoter&AA>&increased&MCY&
production&
A&BCR&=&breakpoint&cluster&
region,&Abl&=&cytoplasmic&
tyrosine&kinase&
A&translocation&causes&hybrid&
BCRAABL&fusion&protein&AA>&
unregulated&cytosolic&tyrosine&
kinase&(ABL&stuck&in&its&active&
form)&
A&TREATMENT&=&imatinib&
mesylate&A&powerful&tyrosine&
kinase&inhibitor&that&binds&to&
the&active&site&of&the&fusion&
protein&bcrAabl&and&prevents&
its&activity&
WT1&is&a&tumor&suppressor&
gene&that&encodes&a&
transcription&factor&important&
in&the&control&of&cell&growth&
and&differentiation.&&
Also&classified&as&
microdeleiton&defect&(PAX6&
locus&chromosome&11)&
A&Rb:&tumor&suppressor&gene&
A&Loss&of&Rb&Destroys&the&G1/S&
Checkpoint:&absent&Rb/&mutant&
Rb&does&NOT&bind&to&E2F&&
Increased&transcription&of&S&
phase&genes&(Unregulated&cell&
division)&

Nikhil&Jain,&Keya&Patel,&Nisha&Patel&

Disease!
Familial&
adenomatous&
polyposis&

Gene!
APC&(adenomatous&
polyposis&coli)&on&
chromosome&5&
&

Inheritance!
1st&hit&is&
inherited&
(familial)&or&
somatic,&2nd&
hit&is&due&to&
methylation&
Familial&AD:&
1st&inherited&
from&mom,&
2nd&hit&is&
somatic&

LiAFraumeni&
Syndrome&

Tp53&

Familial&
Breast/Ovarian&
Cancer&

BRCA1/BRCA2&

Her2+&Breast&
Cancer&

BRCA1/BRCA2&+&
overexpression&of&
Her2&receptor&

Hereditary&
nonpolyposis&colon&
cancer&(Lynch&
Syndrome)&

MSH2,&MLH1&(Code& Familial&AD:&
for&miss&match&
1st&hit&
repair&genes)&
inherited,&2nd&
hit&somatic&

Symptoms!
colorectal&cancer;&multiple&
(>100)&adenomatous&polyps&
develop&throughout&distal&
colon;&&

Rare&disorder&that&greatly&
increases&the&risk&of&cancer&at&a&
young&age;&can&result&in&several&
kinds&of&cancer&including&
breast,&bone,&brain,&
adrenocortical&tumors&and&softA
tissue&carcinomas;&many&
polyps,&progresses&slowly&
Familial&
Incidence&1/12&in&western&
multifactorial& society,&1/3&affected&women&go&
(but&does&
on&to&develop&aggressive&
follow&AD&
tumors,&up&to&20%&have&familial&
cancer&
history,&pancreatic&and&other&
pattern:&1st&
cancers&also&more&common,&
hit&inherited,& male&breast&and&prostate&cancer&
2nd&hit&is&
incidence&also&increased&
somatic)&
Familial&AD:&
&
1st&hit&
inherited,&2nd&
hit&is&somatic&

Genetic!Principles!
loss&of&function,&twoAhit&
hypothesis,&loss&of&
heterozygosity;&very&high&
penetrance;&allelic&
hetereogeneity&

Other!
A&APC&is&a&tumor&suppressor&
gene&(affects&Acatenin&
involved&in&growth&control&
pathway)&

loss&of&function,&twoAhit&
hypothesis,&loss&of&
heterozygosity&

A&P53&is&a&tumor&suppressor&
gene&
A&more&than&half&of&all&families&
with&LiAFraumeni&syndrome&
have&inherited&mutations&in&
the&TP53&gene&

Loss&of&function&(when&
BRCA&is&lost,&cell&can&
duplicate&with&DNA&
damage&and&turn&into&
cancer),&allelic&and&locus&
heterogeneity&

A&Also&classified&as&DNA&repair&
defect:&genes&are&involved&in&
DNA&repair&and&apoptosis&
when&DNA&cant&be&repaired&
A&lifetime&penetrance&about&
85%&for&breast&and&55%&
(BRCA1)&or&25%&(BRCA2)&for&
ovarian&cancer&

&

A&30%&of&breast&cancers&have&
HERA2&amplified&which&form&
double&minute&chromosomes&
A&Herceptin&drug&(antibody)&A&
binds&to&HER2&and&prevents&
binding&of&EGF&to&HER2&
A&Addition&of&Herceptin&to&the&
treatment&results&in&decreased&
tumor&cell&proliferation&
A&Herceptin&is&only&effective&for&
Her2+&tumors&&
A&Microsatellite&instability&
(simple&repetitive&DNA&
sequences)&
A&Also&classified&as&DNA&repair&
defect&

few&polyps,&progresses&rapidly;& &
Tumors&also&exhibit&
microsatellite&instability.&(Short&
repetitive&sequences&of&DNA)&

&

Nikhil&Jain,&Keya&Patel,&Nisha&Patel&

Defect!
Butyrylcholinesterase&
(Pseudocholinesterase)&
deficiency&A&BCHE&gene&

Inheritance!
AR&(pharmacokinetics)&

NAacetyltransferase&2& AR&(pharmacokinetcs)&
deficiency&

CYP2D6&
polymorphism&

AR&(pharmacokinetics)&

Thiopurine&sA
methyltransferase&
polymorphism&

AR&(pharmacokinetics)&

Warfarin&treatment&&A& Pharmacokinetic&+&
CYP2C9&and&VKORC1& pharmacodynamic&
defect&

Pharmacogenomics!
Symptoms!
Patients&with&genetic&variations&in&
butyrylcholinesterase&have&a&decreased&rate&of&
metabolism&of&succinylcholine,&resulting&in&
prolonged&paralysis&
A&Slow&acetylators&are&prone&to&toxicity&of&drugs&
that&are&inactivated&by&acetylation&(homozygous&
recessive):&isoniazid&may&cause&neuropathy&and&
hepatotoxicity,&Hydralazine&(antihypertensive)/&
procainamide&(&antiarrhythmic)&
may&cause&systemic&lupus&erythematosus.&
sulfonamides&may&cause&hypersensitivity&
reactions,&hemolytic&anemia&and&systemic&
lupus&erythematosus.&
A&Fast&acetylators:&metabolize&these&drugs&rapidly&
and&have&low&blood&drug&levels&
A&Poor&metabolizers&are&homozygous&for&recessive&
alleles&coding&for&enzymes&with&low&activityA&suffer&
adverse&effects&when&treated&with&standard&doses&
of&metoprolol;&codeine&is&ineffective&because&it&
cannot&be&converted&to&morphine&
A&Extensive&metabolizers&are&heterozygous&or&
homozygous&for&the&wild&type&allele.&
A&ultrarapid&metabolizers&have&
multiple&copies&of&the&CYP2D6&gene;&require&very&
high&doeses&of&codeine&and&may&overdose&
Homozygotes&for&this&polymorphism&are&at&
increased&risk&for&myelosuppression&when&treated&
with&standards&doses&of&thiopurine&drugs.&Patients&
treated&with&1/10&of&the&standard&dose.&
A&Patients&who&carry&the&variant&alleles&for&CYP2C9&
require&decreased&doses&of&
warfarin&to&achieve&an&anticoagulant&effect,&and&
they&have&increased&risk&for&
hemorrhage&during&warfarin&therapy.&
A&VKORC1&encodes&the&vitamin&K&epoxide&
reductase;&polymorph&affects&dose&requirement&

Other!
A&function:&enzyme&hydrolyzes&succinylcholine&
A&Prolonged&paralysis&from&succinylcholine&caused&
by&abnormal&butyrylcholinesterase&is&treated&with&
continued&mechanical&ventilation&until&muscle&
function&returns&to&normal.&
A&enzyme&catalyzes&the&acetylation&of&
the&antimycobacterial&agent&isoniazid,&hydralazine,&
sulfas&

A&CYP2D6&is&a&member&of&the&cytochrome&P450&
superfamily&of&microsomal,&phase&I&drug&
metabolizing&enzymes&
A&metabolizes&Aadrenergic&blocker&metoprolol,&
antipsychotic&haloperidol,&opioids&codeine&and&
dextromethorphan,&
and&antidepressants&fluoxetine,&imipramine,&and&
desipramine&
A&The&CYP2D6&polymorphism&was&originally&
described&when&studying&debrisoquine&
(antihypertensive)&
and&the&oxytotic&agent&sparteine.&
TPMT&catalyzes&the&SAmethylation&of&the&
anticancer&thiopurines&6Amercaptopurine&and&
azathioprine.&Methylation&of&these&drugs&
inactivates&them&
Warfarin&is&a&racemic&mixture.&SAwarfarin&is&3&A&5&
times&more&potent&than&RAwarfarin.&The&
stereoisomers&are&metabolized&by&different&
enzymes.&Metabolism&of&the&S&isomer&is&mainly&via&
CYP2C9.&Metabolism&of&the&R&isomer&is&via&CYP3A4&
and&other&CYP&isoforms&

Nikhil&Jain,&Keya&Patel,&Nisha&Patel&

Defect!
G6PD&deficiency&

Inheritance!
XR&&has&idiosyncratic&
drug&effects&

Malignant&Hyperemia& AD&
&RYR1&ryanodine&
receptor&gene&defect&

Symptoms!
A&People&with&the&deficiency&are&at&risk&of&oxidative&
stress&due&to&drugs&such&as:&&sulfonamides,&
antimalarials&(primaquine&and&chloroquine)&and&
chloramphenicol&
A&Individuals&develop&acute&and&severe&hemolytic&
anemia.&
A&Hemolytic&anemia&can&also&result&from&the&
ingestion&of&fava&beans.&

Other!
A&Diminished&G6PD&activity&impairs&the&ability&of&
the&cell&to&form&NADPH&that&is&essential&for&the&
maintenance&of&the&reduced&glutathione&pool.&This&
results&in&a&decrease&in&the&cellular&detoxification&
of&free&radicals&and&peroxides&formed&within&the&
cell.&
A&The&most&common&involves&a&cSNP&that&causes&an&
amino&acid&substitution,&resulting&in&a&90%&to&95%&
reduction&of&G6PD&enzyme&function.&The&allele,&AA,&
is&present&in&10%&to&20%&of&Africans&and&is&
thought&to&provide&protection&against&malaria.&
A&Abnormal&RYR1&receptors&trigger&unregulated&
A&one&of&the&leading&causes&of&death&due&to&
release&of&calcium&!&sustained&muscle&contraction& anesthetics&
which&generates&heat,&accelerated&levels&of&aerobic& A&in&vitro&caffeineAhalothane&muscle&contracture&
metabolism&producing&CO2&!&cellular&acidosis,&
test&is&used&to&detect&susceptibility:&small&piece&of&
and&deplete&oxygen&and&ATP.&A&switch&to&
muscle&is&obtained&under&regional&
anaerobic&metabolism&worsens&acidosis&with&the&
or&general&anesthesia&and&attached&to&a&device&
production&of&lactate.&Once&energy&stores&are&
which&measures&the&force&of&contraction;&muscle&
depleted,&the&muscle&fibers&die,&with&
strip&is&then&exposed&to&halothane&or&caffeine&and&
rhabdomyolysis&leading&to&hyperkalemia&and&
response&measured;&a&response&to&halothane&or&a&
myoglobinuria&
response&to&low&concentrations&of&caffeine&are&
A&tachycardia&and&hypertension,&severe&muscle&
diagnostic&for&malignant&hyperthermiaAsusceptible&
rigidity,&hyperthermia,&hyperkalemia,&and&acidA
muscle&
base&imbalance&with&acidosis&when&anesthetics&
like&halothane&are&inhaled&or&patients&are&given&
succinylcholine&

&
&

Nikhil&Jain,&Keya&Patel,&Nisha&Patel&