DISEASE chromosome/gene/protein inheritance symptoms/ phenotype

Williams Syndrome deletion of 26 genes on elfin face, low nasal bridge, cheerful/
Chr 7q ease with strangers, mental retardation
and language difficulties, love for music
, CV problems, supravalvular aortic
stenosis, transient hypercalcemia
Pallister-Killian duplication of Chr 12p craniofacial features, mental retardation
Syndrome , 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 retardation
Recombinant-Chr 3 pericentric Inv(3)
Prader-Willi del Chr 15q imprinted Chr 15q short stature, hypotonia, small hands/
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, severe
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), omphalocele
Syndrome like growth factor 2 gene (abdominal wall defect), visceromegaly,
embyronal tumor in childhood,
hemihyperplasia, renal defects,
adrenocortical cytomegaly, neonatal
hypoglycemia, malignant neoplasms of
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, slow
transl btwn 21q and another usually meiosis 1 motor development, flat face, upward
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 palms,
isochromosomal origin from paternal white spots on iris of eye, poor muscle
, 2% - mosaic down syndrome , chances increase tone, loose ligaments, small hands/feet
either normal or trisomy 21 as maternal age CONGENITAL heart disease, hearing
karyotope, increase (over 35) problems, intestinal problems, celiac
rarely- partial trisomy 21 disease, eye problems (cataracts),
thyroid dysfunction, skeletal problems,
15-fold increase for leukemia/dementia
DISEASE chromosome/gene/protein inheritance symptoms/ phenotype
Trisomy 18 47, +18 meiotic mental retardation, failure to thrive,
(Edwards Syndrome nondisjunction severe heart malformation
postnatal survival rate very low
, clenched fist w/ digits overlapping,
rocker-bottom feet w/ prominent
calcanei, large malformed- low set ears
Trisomy 13 47, +13 meiotic growth retardation, severe mental
(Patau Syndrome) nondisjunction retardation, severe CNS malformations,
congenital heart defects
, bilateral cleft lip, polydactyly (increase
in # of digits)
Cri Du Chat Syndrome mental retardation, microcephaly,
"cry of the cat" del(5p) distinct facies, hypertelorism (excess
width btwn two bodily parts),
epicanthus (prolonged fold of skin over
eye), retrognathia (recession of one or
both jaws- mandibular retrognathia)
Smith-Magenis del(17p) congenital anomalies, mental
Syndrome (SMS) retardation
Charcot-Marie 1400kb dup(17p)/ AD demyelinating neuropathy, progressive
tooth disease peripheral myelin protein weakness and atrophy of distal leg
22 gene (PMP22) muscles
DiGeorge Syndrome Chr 22q microdeletion AD craniofacial anomalies, mental retard.,
(also velocardiofacial heart defects
and conutruncal DGS- absence/hypoplasia of thymus
anomaly face and parathyroid glands, immunodeficiency
syndromes) (T-cell deficiency and hypocalcemia)
22q duplication reciprocal duplication of dysmorphic malformations and birth
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, unambiguous
genitalia
DISEASE chromosome/gene/protein inheritance symptoms/ phenotype
Klinefelter Synd 47, XXY tall/thing w/ long legs, hypogonadism
47, XXY and secondary sexual characteristics
underdeveloped, may have
gynecomastia (male breast), infertile
, learning difficulties and poor
psychosocial adjustment
47, XYY Syndrome 47, XYY not associated with abnormal phenotype
trisomy X 47, XXX not associated with abnormal phenotype
(47, XXX)
Turner Syndrome 45, X infertility, short stature, gonadal
(45, X) dysgenesis, unusual facies, webbed neck
, low posterior hairline, broad chest and
widely spaced nipples, renal/CV anomal
,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, skeletal
neurofibromin-reg intracellular Caf au lait spots (early diagnosis)
processes, act of Ras GTPase, , axillary and inguinal freckling, cutaneous
therefore controls cell neurofibromas, lisch nodules, plexiform
proliferation and tumor suppr. neurofibromas, optic glioma, osseous
legions, predisposed to benign/malignant
tumors of NS
Retinitis Pigmentosa heterozygous mutation in both AD, AR, or X-linked common cause of visual impairment due
ROM1 and perpherin membrane proteins to degeneration of photoreceptors
Cystic fibrosis CFTR gene mutation AR pancreatic insufficiency, progressive
(modifier gene effects- cause lung disease, congenital absence of
variation in forced expiratory vas deferens, sinus infections, poor
volume after 1 second, FEV1) growth, diarrhea, infertility
DISEASE chromosome/gene/protein inheritance symptoms/ phenotype
multiple endocrine RET gene- receptor AD unregulated hyperfunction of kinase
neoplasia type 2A tyrosine kinase, leads to diff leads to dominantly inherited cancer
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 disorder at
(GM2-gangliosidosis 6 months of age
Familial LDL receptor gene mutation AD premature coronary artery disease,
Hypercholesterolemia cutaneous xanthomas (fat deposits)
Achondroplasia Chr 4/ FGFR gene mutation AD short stature, short limbs (rhizomelic),
(short-limb dwarfism low nasal bridge, prominent forehead,
lumbar lordosis, large head,
normal intelligence
Hemophilia A X-linked recessive abnormal blood clot (factor VIII deficiency
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 growth, then
binding protein 2 (mediates rapid onset of neurological symptoms
transcriptional silencing) and loss of milestones btwn 6-8 months
which is a DNA-binding protein of age, become spastic and ataxic, autistic
and irritable w/ outburst cry, wringing/
flapping of arms/hands, seizures (50%),
period of pseudostabilization then leads
to severe retardation and progressive
spasticity, rigidity, scoliosis. Live until
adulthood then unexplained death
DISEASE chromosome/gene/protein inheritance symptoms/ phenotype
dyschondrosteosis SHOX gene- a homeodomain, X-linked dominant skeletal dysplasia, disproportionate
contains TFs that escapes short stature and forearm deformity
X-inactivation
osteogenesis type 1 collagen gene mut. AD abnormal collagen, brittle bones,
imperfecta frequent fractures
Huntington huntingtin gene AD neurological degeneration of striatum
disease (polyglutamine expansion, and cortex, chorea/dystonia,
CAG repeat), 40 or more personality changes, loss of cognition,
death (over a dozen neurological
diseases)
Fragile-X syndrome Xq/ FMR 1 gene (5'-UTR) x-linked but still behavioral abnormalities, hyperactivity
CGG repeat 50-60% penetrance , hand flapping or biting, temper tantrum
to females , poor eye contact, autistic features
Hirschsprung RET, EDNRB, EDN3, GDNF, AD, AR, onset- neonatal to adulthood
disease and NRTN genes. ,mulitgenic, or constipation, abdominal distention,
(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 ganglions
show 100% concord) in submucosal and myenteric plexuses
Myotonic Dystrophy Chr 19/ DMPK (dystrophia AD distal weakness and wasting, facial
(Dystrophia myotonia-protein kinase) weakness and myotonia
myotonia, DM-1) gene- CTG repeat on 3' UTR on cataracts, heart, GI, respiratory muscles,
mRNA mental retardation, diabetes,
hypogonadism
Friedreich-Ataxia frataxin gene in 1st intron AR spinocerebellar ataxia manifests before
(FRDA) (GAA repeats) adolescence
NS- uncoordinated movement, speech
difficulty, decreased tendon reflex,
impairment of position/vibratory senses
cardiomyopathy, scoliosis, foot deformities
Leber hereditary homoplasmic mut of mtDNA mtDNA (maternally spontaneous blindness
optic neuropathy inherited)
DISEASE chromosome/gene/protein inheritance symptoms/ phenotype
idiopathic cerebral factor V Leiden (missense mut) clot formation in venous system of brain
vein thrombosis and prothrombin mutations cause occlusions of cerebral veins
(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 cells
(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 particles is a
constituent of amyloid plaques.
epsilon 4 is a predisposing factor to
alzheimers, but some still never get
it, implicating environmental
factors.
Anencephaly the forebrain, overlying meninges,
vault of the skull, and skin are all absent
, most infants are stillborn
spina bifida failure of fusion of the arches of the
vertebrae with varying degrees of severity
, typically in the lumbar region
cleft lip and palate failure of fusion of frontal process w/
maxillary process at ~35th day of
gestation
nonsyndromic CL(P) can be inherited as single-gene
disorder but commonly a
sporadic case.
congenital heart
defects
coronary artery Fatty streaks, WBCs from internal rupture
disease , calcium scar, WBCs vulnerable to rupture
, rupture releases platelets and fibrin, forms thrombus, MI
occurrence cause misc
elfin face, low nasal bridge, cheerful/ analysis by FISH
ease with strangers, mental retardation
and language difficulties, love for music
, CV problems, supravalvular aortic
stenosis, transient hypercalcemia
craniofacial features, mental retardation unequal crossing
over, abnormal seg
during meiosis in a
carrier of
translocation/invers
6% chance from pericentric Inv(8) Hispanics of SW US
abnormalities/ mental retardation carriers during gametogenesis
dup of distal 3q and originated from
deficiency of 3p Newfoundland
short stature, hypotonia, small hands/ 1/15,000 imprinting,
feet, obesity, mental retardation, live births unimaternal disomy
, microdeletion, or
recombination
unusual facial appearance, severe 1/15,000 births imprinting,
mental retardation, short stature, unipaternal disomy
1/13,700 births
macroglossia (large tongue), omphalocele
(abdominal wall defect), visceromegaly,
adrenocortical cytomegaly, neonatal
hypoglycemia, malignant neoplasms of
1/800 (increase w/ nondisjunction,
delayed language development, slow maternal age) robertsonian trans,
motor development, flat face, upward isochromosomal
eye slant, short neck, abnormally translocation Down
shaped ears, deep crease in palms, syndrome shows
white spots on iris of eye, poor muscle no relationship to
tone, loose ligaments, small hands/feet maternal age, but
CONGENITAL heart disease, hearing high recurrence
problems, intestinal problems, celiac when parent is a
disease, eye problems (cataracts), carrier of translocation
thyroid dysfunction, skeletal problems,
15-fold increase for leukemia/dementia
occurrence cause misc
mental retardation, failure to thrive, 1/3000-7500 maternal age effect 95% of conceptuses
nondisjunction abort spont.
, clenched fist w/ digits overlapping,
rocker-bottom feet w/ prominent
calcanei, large malformed- low set ears
growth retardation, severe mental 1/15,000-25,000 maternal age effect lethal at embryo/
retardation, severe CNS malformations, nondisjunction fetal stages,
50% die 1st month
, bilateral cleft lip, polydactyly (increase and 95% by 1st year
mental retardation, microcephaly, 1/50,000 survival to adulthood
distinct facies, hypertelorism (excess uncommon
epicanthus (prolonged fold of skin over
eye), retrognathia (recession of one or
both jaws- mandibular retrognathia)
aberrant genomic disorder
recombination
demyelinating neuropathy, progressive aberrant genomic disorder
weakness and atrophy of distal leg recombination
craniofacial anomalies, mental retard., 1/2000-4000 aberrant role in 5% of all
homologous congenital heart
DGS- absence/hypoplasia of thymus recombination defects
and parathyroid glands, immunodeficiency
(T-cell deficiency and hypocalcemia)
dysmorphic malformations and birth aberrant homo recomb
ocular coloboma (fissure of eye), aberrant homologous
recombination dup region is inverted
craniofacial anomalies, moderate relative to dup(22)
patients
AZFc region deleted DAZ gene encodes
RNA binding proteins
USP9Y gene- Y linked
de novo mut. leads
to male infertility
prenatal onset, sterility, reduced 1/20,000 point mutation, SRY gene genetically
secondary sexual features, unambiguous deletions, heterozygous
translocations of
SRY gene
occurrence cause misc
tall/thing w/ long legs, hypogonadism 1/1000 male births nondisjunction
and secondary sexual characteristics
gynecomastia (male breast), infertile
not associated with abnormal phenotype 1/1000 male births nondisjunction of
paternal meiosis 2,
prod YY sperm
not associated with abnormal phenotype 1/1000 female nondisjunction
births
infertility, short stature, gonadal 1/4000 female loss or failure to 50% variant cases,
dysgenesis, unusual facies, webbed neck births gain an X-chr. 25% mosaic
, low posterior hairline, broad chest and usually sporadic 99% of fetuses abort
widely spaced nipples, renal/CV anomal spontaneously
ESTROGEN therapy for 2nd sexual development
and decrease risk of osteoporosis
PROGESTERONE therapy to induce menses
onset- prenatal to late childhood 1/3500 births sporadic mutation pleiotropic,
disorder of NS, eyes, skin, skeletal or inheritance variable expressivity
Caf au lait spots (early diagnosis) , loss of function mut
, axillary and inguinal freckling, cutaneous , de novo mutation
neurofibromas, lisch nodules, plexiform , allelic heterogeneity
neurofibromas, optic glioma, osseous
legions, predisposed to benign/malignant
common cause of visual impairment due mut in 43 different locus heterogeneity
to degeneration of photoreceptors loci
pancreatic insufficiency, progressive 1/2000 (mostly 1400 diff mutations allelic heterogeneity
lung disease, congenital absence of caucasian) in CFTR gene , ASO identification
vas deferens, sinus infections, poor (also for sickle cell
mod gene- MBL2-mannose-binding lectin binds
to carbs on pathogens to phagocytize. Worse outcome
if this gene is mutated.
TGFB1- if alleles at this locus are overexpressed,
occurrence cause misc
unregulated hyperfunction of kinase diff mutant alleles phenotypic
leads to dominantly inherited cancer in same gene heterogeneity
neurological degenerative disorder at Ashkenazi Jew carrier
frequency is 1/30
premature coronary artery disease, 1/500 in populations homozygous patients
cutaneous xanthomas (fat deposits) of European/Japanese more severe
descent
short stature, short limbs (rhizomelic), 1/15,000-40,000 gain of function mut paternal age effect
low nasal bridge, prominent forehead, de novo mutation, for guanine de novo
guanine mutated mutation (position 1138)
position (in father's
germline)
abnormal blood clot (factor VIII deficiency
1/3,500 births de novo mutations, genetically lethal
large del/dup, small to affected boys
del, insert, nt since early death and
by fat and fibrotic tissue, skeletal changes no chance of
reproduction
, mosaic expressed in females
normal prenatal/neonatal growth, then 1/10,000-15,000 99% sporadic only exp in females
rapid onset of neurological symptoms female births MECP2 mutation b/c hemizygous males
and loss of milestones btwn 6-8 months 70% from de novo die before birth
of age, become spastic and ataxic, autistic paternal mut
and irritable w/ outburst cry, wringing/ , loss of function incomplete penetrance
flapping of arms/hands, seizures (50%), mutation , variable expressivity
period of pseudostabilization then leads , sex-dependent
to severe retardation and progressive phenotype.
spasticity, rigidity, scoliosis. Live until , only seen in boys w/ somatic
adulthood then unexplained death mosaicism for MECP2 mut or
extra X Chr
occurrence cause misc
skeletal dysplasia, disproportionate ex. Son inherited it via
short stature and forearm deformity pseudoautosomal
inheritance from
father (father originally
received it on X-Chr)
abnormal collagen, brittle bones, gene may exist in
gametes and not in
somatic cells (germline
mosaicism)
others- hemophilia A, B
and DMD
neurological degeneration of striatum 3-7/100,000 for CAG repeat larger expansion
Europeans and 97% inherit mutant leads to earlier
personality changes, loss of cognition, 0.1 to 0.38 /100,000 allele onset.
death (over a dozen neurological for Japanese expansion formed
during paternal
gametogenesis.
behavioral abnormalities, hyperactivity 1/4,000 male births normal repeat= 60 most common form
, hand flapping or biting, temper tantrum (half in females) >200 leads to of heritable mental
, poor eye contact, autistic features 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
constipation, abdominal distention, 2.8/10,000 Asians EDNRB- endothelin B receptor
EDN3- ligand endothelin 3
1/5,000 newborns GDNF-glial cell line-derived neurotrophic factor
congenital absence of ParaNS ganglions (males 2-fold risk)
in submucosal and myenteric plexuses
distal weakness and wasting, facial 1/8,000 (most freq expansion to 1000's LACK penetrance,
adult muscular occurs in female pleiotropy, var exp
cataracts, heart, GI, respiratory muscles, dystrophy) gametogenesis in clinical severity
and age of onset.
normal- 50-80
severe- over 2000
severity increase
and age of onset
decreases.
spinocerebellar ataxia manifests before 1/50,000 mut causes gene normal- 7-34
silencing by disease- 100-1200
NS- uncoordinated movement, speech inducing since mut is in an
difficulty, decreased tendon reflex, heterochromatin intron, there's NO
impairment of position/vibratory senses structure abnormal frataxin protein
cardiomyopathy, scoliosis, foot deformities
homoplasmic mut affected males
of mtDNA DO NOT transmit
the disease
occurrence cause misc
clot formation in venous system of brain genetic and
cause occlusions of cerebral veins environmental
factors
1/1000 per yr genetic and mortality- 10% due
environmental to pulmonary embolus
factors
autoimmunity against own beta cells 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 yoa shows
, ApoE- component of LDL particles is a environmental NO mendelian pattern but DOES show familial aggreg.
factors
epsilon 4 is a predisposing factor to
alzheimers, but some still never get
the forebrain, overlying meninges, 2/3 affected infants multifactorial
vault of the skull, and skin are all absent are female congenital
malformations
failure of fusion of the arches of the multifactorial
vertebrae with varying degrees of severity congenital
malformations
failure of fusion of frontal process w/ common congenital maternal smoking is
maxillary process at ~35th day of malformation a known risk factor
shows familial aggregation
but no mendelian pattern
4-8/1,000 births single-gene or 5 groups
chromosomal 1. flow lesions (familial pattern primarily this type)
mech, exposure to flow lesions about 50% of all CHD,
teratogens (such as , 25% of flow lesions may have del(22q) seen in
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)
Fatty streaks, WBCs from internal rupture kills 450,000 in US males at higher risk
, calcium scar, WBCs vulnerable to rupture per year , mulifactorial disorder- hypertension, obesity, diabetes
, rupture releases platelets and fibrin, forms thrombus, MI , heredity in younger age for MI
, environmental factors- diet, physical act., smoking
, recurrence risk higher when proband is female
ESTROGEN therapy for 2nd sexual development
PROGESTERONE therapy to induce menses
mod gene- MBL2-mannose-binding lectin binds
to carbs on pathogens to phagocytize. Worse outcome
TGFB1- if alleles at this locus are overexpressed,
causes scar/fibrosis after inflammation
GDNF-glial cell line-derived neurotrophic factor
more common form w/ onset after 60 yoa shows
NO mendelian pattern but DOES show familial aggreg.
1. flow lesions (familial pattern primarily this type)
, 25% of flow lesions may have del(22q) seen in
4. abnormalities in extracellular matrix
, mulifactorial disorder- hypertension, obesity, diabetes
, environmental factors- diet, physical act., smoking
, recurrence risk higher when proband is female