genetics diseases

7/21/2019 Genetics Diseases

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DISEASE chromosome/gene/protein inheritance symptoms/ phenotype

Williams Syndrome deletion of 26 genes on elfin face, low nasal bridge, chee

Chr 7q ease with strangers, mental retar

and language difficulties, love for

, CV problems, supravalvular aort

stenosis, transient hypercalcemi

Pallister-Killian duplication of Chr 12p craniofacial features, mental retaSyndrome , other birth defects

Recombinant-8 from carriers w/ 6% of passing on lethal disorder w/ severe cardiac

Syndrome Inv(8)(p23.1q22.1) Inv8 abnormalities/ mental retardatio

Recombinant-Chr 3 pericentric Inv(3)

Prader-Willi del Chr 15q imprinted Chr 15q short stature, hypotonia, small h

Syndrome from father or 30% of feet, obesity, mental retardation,

unimaternal disomy hypogonadism, infertile

(no paternal inher)

Angelman del Chr 15q/ mutation in imprinted Chr 15q unusual facial appearance, sever

Syndrome E6-AP ubiquitin-protein ligase from mother, or 3-5% mental retardation, short stature

gene from unipaternal seizures, spasticity, ataxic gait

disomy

Beckwith- uniparental disomy for usually sporadic, prenatal/ postnatal overgrowth,

Wiedmanne imprinted Chr 11p/ insulin- rarely AD, macroglossia (large tongue), omp

Syndrome like growth factor 2 gene (abdominal wall defect), viscero

embyronal tumor in childhood,

hemihyperplasia, renal defects,adrenocortical cytomegaly, neon

hypoglycemia, malignant neopla

kidney, adrenal, liver

Down Syndrome extra acrocentric Chr 21 or 95% meiotic moderate mental retardation,

(trisomy 21) in 4% w/ 46 chr- robertsonian nondisjunction, delayed language development,

transl btwn 21q and another usually meiosis 1 motor development, flat face, up

acrocentric chr(usually 14 or 22 from maternal and eye slant, short neck, abnormally

, or 21q21q translocation from 10% from meiosis 2 shaped ears, deep crease in palm

isochromosomal origin from paternal white spots on iris of eye, poor m

, 2% - mosaic down syndrome , chances increase tone, loose ligaments, small hand

either normal or trisomy 21 as maternal age CONGENITAL heart disease, heari

karyotope, increase (over 35) problems, intestinal problems, ce

rarely- partial trisomy 21 disease, eye problems (cataracts)

thyroid dysfunction, skeletal pro

15-fold increase for leukemia/de


Trisomy 18 47, +18 meiotic mental retardation, failure to thri

(Edwards Syndrome nondisjunction severe heart malformation


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postnatal survival rate very low

, clenched fist w/ digits overlappi

rocker-bottom feet w/ prominen

calcanei, large malformed- low s

Trisomy 13 47, +13 meiotic growth retardation, severe ment

(Patau Syndrome) nondisjunction retardation, severe CNS malform

congenital heart defects, bilateral cleft lip, polydactyly (in

in # of digits)

Cri Du Chat Syndrome mental retardation, microcephal

"cry of the cat" del(5p) distinct facies, hypertelorism (ex

width btwn two bodily parts),

epicanthus (prolonged fold of ski

eye), retrognathia (recession of o

both jaws- mandibular retrognat

Smith-Magenis del(17p) congenital anomalies, mental

Syndrome (SMS) retardation

Charcot-Marie 1400kb dup(17p)/ AD demyelinating neuropathy, progr

tooth disease peripheral myelin protein weakness and atrophy of distal le

22 gene (PMP22) muscles

DiGeorge Syndrome Chr 22q microdeletion AD craniofacial anomalies, mental re

(also velocardiofacial heart defects

and conutruncal DGS- absence/hypoplasia of thy

anomaly face and parathyroid glands, immuno

syndromes) (T-cell deficiency and hypocalcem

22q duplication reciprocal duplication of dysmorphic malformations and b

syndrome dup(22q) defects

Cat Eye Syndrome quadruple complement of ocular coloboma (fissure of eye),22q (tetrasomy) congenital heart defects,

craniofacial anomalies, moderate

mental retardation

Azoospermia Y-chromosome/AZFc region/ no semen count, infertile

DAZ gene

(AZFc region deleted)

Sex reversal Y-Chr/SRY gene mutation or prenatal onset, sterility, reduced

translocation secondary sexual features, unam

genitalia


Klinefelter Synd 47, XXY tall/thing w/ long legs, hypogona

47, XXY and secondary sexual characteris

underdeveloped, may have

gynecomastia (male breast), infe

, learning difficulties and poor


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psychosocial adjustment

47, XYY Syndrome 47, XYY not associated with abnormal ph

trisomy X 47, XXX not associated with abnormal ph

(47, XXX)

Turner Syndrome 45, X infertility, short stature, gonadal(45, X) dysgenesis, unusual facies, webb

, low posterior hairline, broad ch

widely spaced nipples, renal/CV

,slight decreased intelligence,

lymphedema of hands/feet

Neurofibromatosis Chr 17/ NF1 gene/ AD onset- prenatal to late childhood

(NF1) neurofibromin protein defect disorder of NS, eyes, skin, skeleta

neurofibromin-reg intracellular Caf au lait spots (early diagnosis

processes, act of Ras GTPase, , axillary and inguinal freckling, c

therefore controls cell neurofibromas, lisch nodules, ple

proliferation and tumor suppr. neurofibromas, optic glioma, oss

legions, predisposed to benign/m

tumors of NS

Retinitis Pigmentosa heterozygous mutation in both AD, AR, or X-linked common cause of visual impairm

ROM1 and perpherin membrane proteins to degeneration of photorecepto

Cystic fibrosis CFTR gene mutation AR pancreatic insufficiency, progress

(modifier gene effects- cause lung disease, congenital absence

variation in forced expiratory vas deferens, sinus infections, po

volume after 1 second, FEV1) growth, diarrhea, infertility


multiple endocrine RET gene- receptor AD unregulated hyperfunction of kin

neoplasia type 2A tyrosine kinase, leads to diff leads to dominantly inherited ca

and 2B loss of function or hyperfunction of thyroid and adrenal glands

of the kinase which can lead

to different phenotypes and

diseases

Tay-Sachs AR neurological degenerative disord

(GM2-gangliosidosis 6 months of age

Familial LDL receptor gene mutation AD premature coronary artery disea

Hypercholesterolemia cutaneous xanthomas (fat deposi

Achondroplasia Chr 4/ FGFR gene mutation AD short stature, short limbs (rhizom

(short-limb dwarfism low nasal bridge, prominent fore

lumbar lordosis, large head,

normal intelligence


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Hemophilia A X-linked recessive abnormal blood clot (factor VIII d

Duchenne-Muscular dystrophin gene X-linked progressive

Dystrophy (DMD) an intracellular protein in muscular myopathy

(Beck 1, 2 is less smooth, skeletal, cardiac mm. , muscle tissue wasting replaced

severe form) by fat and fibrotic tissue, skeletal

deformities, paralysis, death

Rett Syndrome MECP2 gene/ methyl CpG X-linked dominant normal prenatal/neonatal growt

binding protein 2 (mediates rapid onset of neurological symp

transcriptional silencing) and loss of milestones btwn 6-8

which is a DNA-binding protein of age, become spastic and ataxi

and irritable w/ outburst cry, wri

flapping of arms/hands, seizures

period of pseudostabilization the

to severe retardation and progre

spasticity, rigidity, scoliosis. Live

adulthood then unexplained deat


dyschondrosteosis SHOX gene- a homeodomain, X-linked dominant skeletal dysplasia, disproportiona

contains TFs that escapes short stature and forearm defor

X-inactivation

osteogenesis type 1 collagen gene mut. AD abnormal collagen, brittle bones,

imperfecta frequent fractures

Huntington huntingtin gene AD neurological degeneration of stri

disease (polyglutamine expansion, and cortex, chorea/dystonia,

CAG repeat), 40 or more personality changes, loss of cogni

death (over a dozen neurological

diseases)

Fragile-X syndrome Xq/ FMR 1 gene (5'-UTR) x-linked but still behavioral abnormalities, hypera

CGG repeat 50-60% penetrance , hand flapping or biting, temper

to females , poor eye contact, autistic featur

Hirschsprung RET, EDNRB, EDN3, GDNF, AD, AR, onset- neonatal to adulthood

disease and NRTN genes. ,mulitgenic, or constipation, abdominal distenti


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(neurocristopathy) three loci are located at multifactorial enterocolitis, impaired intestinal

10q11.2 (RET), 3p21, and 19q12 (risk for sibs is high, motility (incapable of peristalsis)

MZ twins does not congenital absence of ParaNS ga

show 100% concord) in submucosal and myenteric ple

Myotonic Dystrophy Chr 19/ DMPK (dystrophia AD distal weakness and wasting, faci

(Dystrophia myotonia-protein kinase) weakness and myotonia

myotonia, DM-1) gene- CTG repeat on 3' UTR on cataracts, heart, GI, respiratorymRNA mental retardation, diabetes,

hypogonadism

Friedreich-Ataxia frataxin gene in 1st intron AR spinocerebellar ataxia manifests

(FRDA) (GAA repeats) adolescence

NS- uncoordinated movement, s

difficulty, decreased tendon refle

impairment of position/vibratory

cardiomyopathy, scoliosis, foot d

Leber hereditary homoplasmic mut of mtDNA mtDNA (maternally spontaneous blindness

optic neuropathy inherited)


idiopathic cerebral factor V Leiden (missense mut) clot formation in venous system

vein thrombosis and prothrombin mutations cause occlusions of cerebral vein

(3' UTR)

deep venous FVL and prothromin mutations thrombosis of lower extremities

thrombosis

Type 1 diabetes genetic factor- MHC class 2 autoimmunity against own beta

(IDDM) locus (HLA-DR3 and HLA-DR4 of pancreas that prod insulin.

are linked to susceptible

DRB1 and DQB1, respectively).

MHC haplotypes include

insulin, CTLA4, and PTPN22

genes.

Alzheimer disease Chr 19/ APOE gene/ fatal neurodegenerative disease

epsilon 2, 3, 4 alleles , ApoE- component of LDL particl

constituent of amyloid plaques.

epsilon 4 is a predisposing factor

alzheimers, but some still never

it, implicating environmental

factors.

Anencephaly the forebrain, overlying menin

vault of the skull, and skin are all

, most infants are stillborn


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spina bifida failure of fusion of the arches

vertebrae with varying degrees o

, typically in the lumbar region

cleft lip and palate failure of fusion of frontal proces

maxillary process at ~35th day of

gestation

nonsyndromic CL(P) can be inherited as single-genedisorder but commonly a

sporadic case.

congenital heart

defects

coronary artery Fatty streaks, WBCs from internal

disease , calcium scar, WBCs vulnerable to r

, rupture releases platelets and fibrin,


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occurrence cause misc

ful/ analysis by FISH

dation

music

ic

rdation unequal crossingover, abnormal seg

during meiosis in a

carrier of

translocation/invers

6% chance from pericentric Inv(8) Hispanics of SW US

n carriers during gametogenesis

dup of distal 3q and originated from

deficiency of 3p Newfoundland

nds/ 1/15,000 imprinting,

live births unimaternal disomy

, microdeletion, or

recombination

1/15,000 births imprinting,

, unipaternal disomy

1/13,700 births

halocele

egaly,

atal

ms of

1/800 (increase w/ nondisjunction,

low maternal age) robertsonian trans,

ward isochromosomal

translocation Down

s, syndrome shows

uscle no relationship to

s/feet maternal age, but

ng high recurrence

liac when parent is a

, carrier of translocation

lems,

entia


ive, 1/3000-7500 maternal age effect 95% of conceptuses

nondisjunction abort spont.


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ng,

t ears

al 1/15,000-25,000 maternal age effect lethal at embryo/

ations, nondisjunction fetal stages,

50% die 1st month crease and 95% by 1st year

, 1/50,000 survival to adulthood

ess uncommon

over

ne or

ia)

aberrant genomic disorder

recombination

essive aberrant genomic disorder

g recombination

tard., 1/2000-4000 aberrant role in 5% of all

homologous congenital heart

us recombination defects

eficiency

ia)

irth aberrant homo recomb

aberrant homologousrecombination dup region is inverted

relative to dup(22)

patients

AZFc region deleted DAZ gene encodes

RNA binding proteins

USP9Ygene- Y linked

de novo mut. leads

to male infertility

1/20,000 point mutation, SRY gene genetically

biguous deletions, heterozygous

translocations of

SRY gene


dism 1/1000 male births nondisjunction

tics

tile


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enotype 1/1000 male births nondisjunction of

paternal meiosis 2,

prod YY sperm

enotype 1/1000 female nondisjunction

births

1/4000 female loss or failure to 50% variant cases,d neck births gain an X-chr. 25% mosaic

st and usually sporadic 99% of fetuses abort

nomal spontaneously

ESTROGENtherapy for 2nd sexual dev

and decrease risk of osteoporosis

PROGESTERONEtherapy to induce me

1/3500 births sporadic mutation pleiotropic,

l or inheritance variable expressivity

) , loss of function mut

taneous , de novo mutation

xiform , allelic heterogeneity

ous

alignant

ent due mut in 43 different locus heterogeneity

rs loci

ive 1/2000 (mostly 1400 diff mutations allelic heterogeneity

of caucasian) in CFTR gene , ASO identification

or (also for sickle cell

mod gene- MBL2-mannose-binding le

to carbs on pathogens to phagocytize.if this gene is mutated.

TGFB1- if alleles at this locus are over


ase diff mutant alleles phenotypic

cer in same gene heterogeneity

er at Ashkenazi Jew carrier

frequency is 1/30

e, 1/500 in populations homozygous patients

ts) of European/Japanese more severe

descent

elic), 1/15,000-40,000 gain of function mut paternal age effect

ead, de novo mutation, for guanine de novo

guanine mutated mutation (position 1138)

position (in father's


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germline)

eficiency

1/3,500 births de novo mutations, genetically lethal

large del/dup, small to affected boys

del, insert, nt since early death and

changes no chance of

reproduction, mosaic expressed in females

, then 1/10,000-15,000 99% sporadic only exp in females

oms female births MECP2 mutation b/c hemizygous males

onths 70% from de novo die before birth

, autistic paternal mut

ging/ , loss of function incomplete penetrance

(50%), mutation , variable expressivity

n leads , sex-dependent

ssive phenotype.

ntil , only seen in boys w/ somatic

h mosaicism for MECP2 mut or

extra X Chr


te ex. Son inherited it via

ity pseudoautosomal

inheritance from

father (father originally

received it on X-Chr)

gene may exist in

gametes and not in

somatic cells (germlinemosaicism)

others- hemophilia A, B

and DMD

tum 3-7/100,000 for CAG repeat larger expansion

Europeans and 97% inherit mutant leads to earlier

tion, 0.1 to 0.38 /100,000 allele onset.

for Japanese expansion formed

during paternal

gametogenesis.

ctivity 1/4,000 male births normal repeat= 60 most common form

antrum (half in females) >200 leads to of heritable mental

es methylation of retardation. (2nd to

FMR1 promoter Down syndrome

(expansion to over of male causation)

200 occurs in haplotype effect,

female gametogen) somatic mosaicism

1.8/10,000 European RET- tyrosine kinase receptor

n, 2.8/10,000 Asians EDNRB- endothelin B receptor


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EDN3- ligand endothelin 3

1/5,000 newborns GDNF-glial cell line-derived neurotro

glions (males 2-fold risk)

xuses

al 1/8,000 (most freq expansion to 1000's LACK penetrance,

adult muscular occurs in female pleiotropy, var exp

uscles, dystrophy) gametogenesis in clinical severityand age of onset.

normal- 50-80

severe- over 2000

severity increase

and age of onset

decreases.

before 1/50,000 mut causes gene normal- 7-34

silencing by disease- 100-1200

eech inducing since mut is in an

x, heterochromatin intron, there's NO

senses structure abnormal frataxin protein

eformities

homoplasmic mut affected males

of mtDNA DO NOT transmit

the disease


f brain genetic and

environmental

factors

1/1000 per yr genetic and mortality- 10% due

environmental to pulmonary embolusfactors

ells 1/500 of the white genetic and

population environmental

(rarely occurs alone)

1-2% of US popul. genetic and more common form w/ onset after 60

es is a environmental NO mendelian pattern but DOES show

factors

to

et

es, 2/3 affected infants multifactorial

absent are female congenital

malformations


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f the multifactorial

f severity congenital

malformations

s w/ common congenital maternal smoking is

malformation a known risk factor

shows familial aggregationbut no mendelian pattern

4-8/1,000 births single-gene or 5 groups

chromosomal 1. flow lesions (familial pattern primar

mech, exposure to flow lesions about 50% of all CHD,

teratogens (such as , 25% of flow lesions may have del(22

rubella infection or velocardiofacial patients)

maternal diabetes) 2. defects in cell migration

. Usually cause is 3. defects in cell death

unknown 4. abnormalities in extracellular matrix

(may be 5. defects in targeted growth

multifactorial in

origin)

rupture kills 450,000 in US males at higher risk

upture per year , mulifactorial disorder- hypertension,

orms thrombus, MI , heredity in younger age for MI

, environmental factors- diet, physical

, recurrence risk higher when proband


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elopment

nses

tin binds

Worse outcome

xpressed,

causes scar/fibrosis after inflammation


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phic factor

yoa shows

familial aggreg.


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ily this type)

) seen in

obesity, diabetes

act., smoking

is female

genetics diseases

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