Comprehensive survey of human genetic diseases
-
Upload
enharmonic-melodies -
Category
Documents
-
view
649 -
download
4
Transcript of Comprehensive survey of human genetic diseases
![Page 1: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/1.jpg)
Medical GeneticsMedical Genetics
For Medical StudentFor Medical Student
![Page 2: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/2.jpg)
Overview
![Page 3: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/3.jpg)
Importance of Genetics to Medicine >12 million Americans with genetic disorders (GD)
80% of MR in America due to genetic component
2-3% background population risk for a major birth defect (BD)
15% overall miscarriage risk for any pregnancy
25-50% first trimester miscarriage risk
30-50% first trimester losses due to chromosome anomalies
>30% pediatric hospital admissions due to GD
GD affect all major systems, any age, any race, male or female
![Page 4: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/4.jpg)
Importance of Genetics to Medicine
Changing focus of medicine:
primary care physicians vs specialists
prevention vs treatment
genetic causation for both rare and common diseases
Human Genome Project
designer drugs
Problem based approach taken in medical schools
Genetics as the link between basic research & clinical observation
![Page 5: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/5.jpg)
Importance of Genetics to Medicine
Triple theme: genetic traits as they segregate through families
allows insights into health of the population
flow of info from DNA to RNA to protein links genetics to physiology
ethical issues linked to treatment, therapy options, research, decision-making and quality of life
![Page 6: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/6.jpg)
Terms & Definitions
birth defect genetic disorder malformation deformation disruption sequence syndrome association morphology dysmorphology
variability heterogeneity pleiotrophy organogenesis morphogenesis hyperplasia hypoplasia dysplasia
![Page 7: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/7.jpg)
Pedigree Symbols
See text for additional symbols:
normal male/female deceasedunknown sex stillbirthaffected male/female miscarriage (Sab)marriage/mating line termination of pregnancy
(Tab)illegitimacy line pregnancyconsanguineous mating consultandidentical/fraternal twins proband
![Page 8: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/8.jpg)
Modes of Inheritance & Selected Examples
![Page 9: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/9.jpg)
Heritable Birth Defects (HBD)
Single Gene Defects (SGD) Chromosomal Anomalies (CA) Multifactorial Inheritance (MF) Non-Classical Inheritance (NCI) Cancer Genetics (CG)
![Page 10: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/10.jpg)
“Non-Heritable” Birth Defects (NHBD)
Environmental teratogensteratogen = any chemical,
biological or physical agent that increases the probability of a birth defect
![Page 11: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/11.jpg)
Heritable Birth DefectsHeritable Birth Defects (HBD)(HBD)
Single Gene DefectsChromosomal AbnormalitiesMultifactorial DisordersNon-classical DisordersCancer Genetics
![Page 12: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/12.jpg)
Single Gene DefectsSingle Gene Defects
Autosomal recessive Autosomal dominantX-linked recessive
X-linked dominant
HBD
![Page 13: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/13.jpg)
Autosomal recessive (AR)
One trait, 2 allelesA = dominant normal allelea = recessive abnormal allele
Homozygous dominant = normal (AA)
Heterozygous dominant = normal, carrier (Aa)
Homozygous recessive = affected (aa)
HBD/SGD/AR
![Page 14: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/14.jpg)
Autosomal recessive Carrier parents Normal parental
phenotype 75% chance for normal
offspring 25% chance for affected
offspring Males & females equally
affected “Inborn errors of
metabolism” Associated with specific
ethnic groups
HBD/SGD/AR
![Page 15: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/15.jpg)
AR Pedigree
Pedigree symbols Proband “Horizontal” Equal numbers of
males and females Phenotypically normal
parents 25% recurrence risk
HBD/SGD/AR
![Page 16: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/16.jpg)
AR Disorders PKU - phenylketonuria Galactosemia Homocystinuria Cystic fibrosis Tay-Sachs Sickle cell anemia
HBD/SGD/AR
![Page 17: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/17.jpg)
AR Disorders & Ethnicity
Cystic fibrosis Tay-Sachs Sickle cell
anemia Thalassemia
Caucasians Ashkenazai Jews African Americans Mediterraneans
(ex:Greeks/Italians)
HBD/SGD/AR
![Page 18: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/18.jpg)
Inborn Errors of MetabolismPhenylpyruvic acid 1Phenylalanine DOPA DOPA Quinone 2 3Tyrosine
P-hydroxyphenylpyruvic acid Homogentisic acid
4
Thyroid HormoneMaleylacetoacetic acid
1 = tyrosinase/albinism 3 = tyrosinase/albinism 2 = phenylalanine hydroxylase/PKU 4 = homogentisic acid
oxidase/alcaptonuria
HBD/SGD/AR
![Page 19: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/19.jpg)
Inborn Errors of MetabolismInborn Errors of Metabolism General Characteristics
mental retardation hypopigmentation dislocated lens osteoporosis renal stones coarse facies and hair self-mutilation acute acidosis
unusual body odor unusual odor to urine family history of early death seizures overwhelming neonatal illness massive ketosis severe vomiting persistent hiccups
![Page 20: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/20.jpg)
PhenylketonuriaPKU
![Page 21: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/21.jpg)
PKU Major Clinical Features
MR Agitated behavior EEG abnormalities hyperactive reflexes muscular hypertonicity
inability to talk inability to walk tremors seizures
![Page 22: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/22.jpg)
Tay-Sachs Disease
![Page 23: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/23.jpg)
Tay-Sachs Major Clinical Features
psychomotor retardation psychomotor deterioration blindness apathy unresponsive hypotonia seizures EEG abnormalities megalencephaly absence of hexosaminidase A early death (2-4 years)
![Page 24: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/24.jpg)
Cystic Fibrosis
![Page 25: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/25.jpg)
CF Major Clinical Features defect of chloride ion transport increased exocrine mucous secretions salty-tasting skin persistent cough increased risk for pulmonary infections:
early: S. aures, H. influenzae, S. pneumonia late: P. aeruginosa
pneumonia poor weight gain despite excessive appetite bulky, foul-smelling stools clubbed fingers normal intelligence
![Page 26: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/26.jpg)
CFTR Gene (Cystic Fibrosis Transmembrane Regulator)
250 kb encodes 1480 amino acid protein mutation first discovered in position 508 abnormal transport of chloride ions increased Cl- ions inside cell water enters cell by osmosis exterior of cell very viscous/mucous
![Page 27: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/27.jpg)
Niemann-Pick Disease
![Page 28: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/28.jpg)
NP Major Clinical Features
onset at 6 months foamy histiocytes in bone marrow failure to thrive mental retardation cherry-red macular spots respiratory infections hepatosplenomegaly absence of sphingomyelinase death by age 3
![Page 29: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/29.jpg)
MucopolysaccharidosesMPS
![Page 30: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/30.jpg)
MPS General Clinical Features
mental retardation frontal bossing hypertelorism prominent eyes gingival hypertrophy gapped teeth thick tongue storage of
mucopolysaccharides in body tissues
corneal clouding hepatosplenomegaly hand anomalies still joints congestive heart failure pneumonia kyphosis
![Page 31: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/31.jpg)
Hurler’s SyndromeMPS Type 1
![Page 32: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/32.jpg)
Hurler Major Clinical Features
growth retardation macrocephaly coarse facies full lips low nasal bridge corneal clouding abnormal teeth and
tongue
short, misshapen bones joint deformities thickening of coronary vessels hepatosplenomegaly hernias deafness
![Page 33: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/33.jpg)
Sanfilippo SyndromeMPS Type 111
![Page 34: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/34.jpg)
Sanfilippo Major Clinical Features
accelerated growth to 3 years growth retardation after 3 years mental deterioration mildly coarse facies variable hepatomegaly abnormal teeth mild cardiac anomalies
![Page 35: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/35.jpg)
Scheie’s SyndromeMPS Type V
![Page 36: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/36.jpg)
Scheie’s Major Clinical Features
normal intelligence corneal clouding joint limitation in hands aortic valvular defect body hirsutism hernias broad hands and feet
![Page 37: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/37.jpg)
von Gierke’s Disease (Glycogen Storage Disorder Type I)
![Page 38: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/38.jpg)
Von Gierke’s Major Clinical Features
absence of liver glucose–6-phosphatase
hypoglycemia short stature good prognosis accumulation of glycogen in liver and
kidneys
![Page 39: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/39.jpg)
Ehlers-Danlos Syndrome
![Page 40: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/40.jpg)
Ehlers-Danlos Major Clinical Features
hypermobile “lop” ears velvety skin fragile hyperextensive skin hyperextensible joints easy to bruise mitral valve prolapse collagen defect
![Page 41: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/41.jpg)
Progeria
![Page 42: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/42.jpg)
Progeria Major Clinical Features
alopecia thin skin hypoplasia of nails loss of subcutaneous fat skeletal hypoplasia,
dysplasia, degeneration
delayed eruption of teeth atherosclerosis mild elevation of serum
cholesterol premature aging normal intelligence
![Page 43: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/43.jpg)
Spinal Muscular Atrophy Type I (Werdnig-Hoffman Disease)
![Page 44: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/44.jpg)
SMA Type I Clinical Features
hypotonia weakness decreased or absent deep tendon
reflexes pulmonary infection respiratory failure rapid coarse to death at early age
![Page 45: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/45.jpg)
Homocystinuria
![Page 46: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/46.jpg)
Homocystinuria Clinical Features
abnormalities of skeletal system
genu valgum scoliosis kyphosis pectus excavatum
osteoporosis restricted joint mobility ectopia lentis (downward) thrombosis mental retardation
![Page 47: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/47.jpg)
Single Gene DefectsSingle Gene Defects
Autosomal recessive Autosomal dominant
X-linked recessiveX-linked dominant
![Page 48: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/48.jpg)
Autosomal dominant (AD)
One Trait, 2 allelesA = dominant abnormal allelea = recessive normal allele
Homozygous dominant = affected, often lethal (AA) Heterozygous dominant = affected (Aa)Homozygous recessive = normal (aa)
HBD/SGD/AD
![Page 49: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/49.jpg)
Autosomal Dominant (AD) One parent affected (usually
heterozygous) Second parent normal 50% chance for affected
offspring 50% chance for normal offspring Males and females equally
affected Penetrance Variable expression
HBD/SGD/AD
![Page 50: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/50.jpg)
AD Pedigree “Vertical”
Equal numbers of males and females affected
One parent genotypically & phenotypically normal
Other parent heterozygous affected
50% recurrence risk
HBD/SGD/AD
![Page 51: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/51.jpg)
AD Disorders
Marfan’s Syndrome Huntington’s Chorea Osteogenesis imperfecta
Neurofibromatosis
Retinoblastoma Tuberous sclerosis Apert’s Syndrome Multiple polyposis of
colon
HBD/SGD/AD
![Page 52: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/52.jpg)
Marfan Syndrome
![Page 53: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/53.jpg)
Marfan Clinical Features
abnormalities of skeletal system
kyphoscoliosis pectus excavatum ectopia lentis
(upward) myopia
dilation of ascending aorta
mitral regurgitation dissecting aneurysm retinal detachment small lens
![Page 54: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/54.jpg)
Crouzon’s Syndrome
![Page 55: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/55.jpg)
Crouzon Major Clinical Features
shallow orbits premature craniosynostosis maxillary hypoplasia frontal bossing conductive hearing loss mental retardation (occasional) seizures (occasional)
![Page 56: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/56.jpg)
Apert’s Syndrome
![Page 57: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/57.jpg)
Apert Major Clinical Features
mental deficiency occasional normal intelligence irregular craniosynostosis (“Tower” skull) midfacial hypoplasia syndactyly (“mitten hand”) hypertelorism strabismus small nose maxillary hypoplasia
![Page 58: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/58.jpg)
Treacher-Collin’s Syndrome
![Page 59: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/59.jpg)
Treacher-Collin Clinical Features
mandibular hypoplasia lower lid colomboma malformation of auricles malar hypoplasia (with or
without cleft in zygomatic bone)
external ear canal defect conductive deafness cleft palate incompetent soft palate
![Page 60: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/60.jpg)
Cherubism
![Page 61: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/61.jpg)
Cherubism Major Clinical Features
tumor-like facial changes benign dysplasia of jaw bone serious dental anomalies
![Page 62: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/62.jpg)
Neurofibromatosis
![Page 63: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/63.jpg)
Neurofibromatosis Major Clinical Features
neurofibromas of skin, CNS, eye, stomach, liver, intestine, kidney, bladder, larynx
“café-au-lait” spots kyphoscoliosis feeble-minded
(occasional)
abnormal pigmentationof skin
iris hamartomas (Lischnodules)
tumorous partialgiantism (occasional)
![Page 64: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/64.jpg)
Achondroplastic Dwarfism
![Page 65: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/65.jpg)
Achondroplastic Dwarfism Major Clinical Features
megalocephaly short limbs low nasal bridge caudal narrowing of
spinal cord
lumbar lordosis skeletal anomalies mild hypotonia normal intelligence
![Page 66: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/66.jpg)
Osteogenesis Imperfecta
![Page 67: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/67.jpg)
Osteogenesis Imperfecta Major Clinical Features
“congenita” = severe form
multiple intrauterine fractures
“tarda” = later onset form
susceptibility to bone fracture
bone deformities joint laxity
short stature growth retardation kyphoscoliosis pectus excavatum yellow teeth thin skin blue sclerae
![Page 68: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/68.jpg)
Holt-Oram Syndrome
![Page 69: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/69.jpg)
Holt-Oram Major Clinical Features
defect of upper limb and shoulder girdle thumb hypoplasia or phocomelia asymmetry auricular septal defect cardiac arrythmia hypoplasia of distal blood vessels
![Page 70: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/70.jpg)
Single Gene DefectsSingle Gene Defects
Autosomal recessive Autosomal dominant
X-linked recessiveX-linked dominant
![Page 71: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/71.jpg)
X-linked recessive (XR)
One trait, 2 allelesA = dominant normal allelea = recessive abnormal allele
Must consider which parent has the abnormal gene when assessing risk
HBD/SGD/XR
![Page 72: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/72.jpg)
X-linked recessive (XR)
Homozygous dominant = normal female (XAXA) Heterozygous dominant = normal female carrier (XAXa) Homozygous recessive = affected female (XaXa)
Hemizygous dominant = normal male (XAY) Hemizygous recessive = affected male (XaY)
HBD/SGD/XR
![Page 73: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/73.jpg)
X-linked recessive (XR)
Heterozygous normal mother (carrier)
Hemizygous normal father50% risk for an affected male50% risk for a normal male
100% chance for normal female: 50% carrier female 50% homozygous normal female
Males and females NOT equally affected
HBD/SGD/XR
![Page 74: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/74.jpg)
XR Pedigree
“Criss-cross” inheritance pattern
Female carriers risk affected sons
Female carriers risk carrier daughters
Often lethal to males
Transmission through normal females producing affected males
No male to male transmission
HBD/SGD/XR
![Page 75: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/75.jpg)
XR Pedigree
“Criss-cross” inheritance pattern
Female carriers risk affected sons
Female carriers risk carrier daughters
Often lethal to males
Transmission through normal females producing affected males
No male to male transmission
HBD/SGD/XR
![Page 76: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/76.jpg)
XR Disorders
Duchenne’s Muscular Dystrophy Hemophilia Hunter’s Syndrome Aarskog’s Syndrome Lesch-Nyhan Syndrome Pyruvate dehydrogenase deficiency
HBD/SGD/XR
![Page 77: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/77.jpg)
Muscular Dystrophy
![Page 78: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/78.jpg)
Muscular Dystrophy Major Clinical Features
hypotonia frequent stumbling difficulty climbing stairs difficulty getting up from floor pseudohypertrophy of calf muscles skeletal muscular weakness inability to walk between ages 5 and
15 absence of dystrophin protein death by age 20
![Page 79: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/79.jpg)
Aarskog Syndrome
![Page 80: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/80.jpg)
Aarskog Major Clinical Features
round face small nose brachydactyly slight to moderate
short stature
mild pectus excavatum prominent umbilicus shawl scrotum dull normal intelligence hypodontia
![Page 81: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/81.jpg)
Lesch-Nyhan Syndrome
![Page 82: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/82.jpg)
Lesch-Nyhan Major Clinical Features
spasticity choreoathetosis self-mutilation autistic behavior growth deficiency gout HGPRT deficiency (enzyme of purine
metabolism)
![Page 83: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/83.jpg)
Hunter Syndrome(MPS Type II)
![Page 84: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/84.jpg)
Hunter Major Clinical Features
coarse facies growth retardation stiff joints no corneal clouding neurological
deterioration severe mental
retardation
macrocephaly hepatosplenomegaly hernias progressive deafness abnormal dentition
![Page 85: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/85.jpg)
Bruton’s Agammaglobulinemia
![Page 86: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/86.jpg)
Bruton Major Clinical Features
normal appearance absence of serum antibodies risk of bacterial infection risk of pneumonia strong predisposition to rheumatoid
arthritis and to cancer
![Page 87: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/87.jpg)
Single Gene DefectsSingle Gene Defects
Autosomal recessive Autosomal dominantX-linked recessive
X-linked dominant
![Page 88: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/88.jpg)
X-linked dominant (XD)
One trait, 2 allelesA = dominant abnormal allelea = recessive normal allele
Must consider which parent has the abnormal gene when assessing risk
HBD/SGD/XD
![Page 89: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/89.jpg)
X-linked dominant (XD)
Homozygous dominant = affected female (XAXA) Heterozygous dominant = affected female (XAXa)
Homozygous recessive = normal female (XaXa)
Hemizygous dominant = affected male (XAY) Hemizygous recessive = normal male (XaY)
HBD/SGD/XD
![Page 90: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/90.jpg)
X-Linked Dominant (XD)
For heterozygous affected females:50% risk for affected son50% risk for affected daughter
For hemizygous affected males:100% risk for affected daughter0% risk for affected son
Males and females NOT equally affected
HBD/SGD/XD
Affected Father
Normal Mother
Affected Normal Affected Normal female male female male
![Page 91: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/91.jpg)
XD Pedigree
Homozygous females often more severely affected than hemizygous males
Affected females risk affected sons and affected daughters
Affected males risk affected daughters
No male to male transmission
Difficult to distinguish from autosomal dominant
HBD/SGD/XD
![Page 92: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/92.jpg)
XD Disorders
Vitamin D resistant rickets Browning of the enamel of the teeth Albright’s hereditary osteodystrophy Taybi Syndrome
HBD/SGD/XD
![Page 93: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/93.jpg)
Vitamin D-resistant Rickets with hypophosphatemia
![Page 94: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/94.jpg)
Resistant Rickets Major Clinical Features
bone deficiencies (“bowed” legs) dental anomalies decreased phosphate in serum short stature normal intelligence
![Page 95: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/95.jpg)
Heritable Birth DefectsHeritable Birth Defects
Single Gene Defects Chromosomal Abnormalities
Multifactorial DisordersNon-classical DisordersCancer Genetics
![Page 96: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/96.jpg)
Populations at Risk for Chromosome Errors spontaneous abortuses sexually ambiguous organisms infertile males or females newborns with multiple congenital anomalies mentally retarded mentally ill behaviorally disordered
specific cancers:Ataxia telangiectasia CMLBloom’s Syndrome Burkitt’s lymphomaFanconi’s anemia NeurofibromatosisXeroderma pigmentosum RetinoblastomaFamilial adenomatous polyposis Gardner’s Syndrome
Bruton’s agammaglobulinemia Wiskott-Aldrich Syndrome
![Page 97: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/97.jpg)
Chromosome Preparation & Analysis
Obtain sample (eg: blood) Add WBC to chromosome media with mitogens (eg: PHA) Incubate at 37 degrees C (minimum of 3 days) Harvest after adding colchicine to arrest in metaphase Add fix (methanol:acetic acid) Prepare slides Treat with trypsin and Giemsa to induce G bands
![Page 98: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/98.jpg)
Chromosome Banding
G bands C bands (centromere) Q bands (fluorescent equivalent to G) R bands (opposite pattern of G and Q) High resolution banding (>400 bands/haploid
set) FISH (fluorescent in situ hybridization) CGH (comparative genomic hybridization)
![Page 99: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/99.jpg)
Chromosomes: A Review
Homologous pairs
Autosomes/sex chromosomes
Karyotype: arrange by size
Centromere position:metacentricsubmetacentric/p/qacrocentric/satellites/rDNA
G Banding
Nomenclature
HBD/CA
![Page 100: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/100.jpg)
Normal Female: 46,XX
![Page 101: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/101.jpg)
Normal Male: 46,XY
![Page 102: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/102.jpg)
Acrocentric chromosome having a “bad hair day”
Note chromatids
“Fibrous” appearance
No bands apparent
Chromosomes: A Review
HBD/CA
![Page 103: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/103.jpg)
Chromosomes: A Review
Idiogram:
standard for bands p and q arms centromere position bands numbered satellited chromosomes
HBD/CA
![Page 104: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/104.jpg)
Chromosomes: A Review
chromosome #1 idiogram
largest, metacentric p and q arms with bands
and sub-bands
different band density shown
G-banded metaphase chromosome at lower left
HBD/CA
p
q
3
2
1
1
2
34
![Page 105: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/105.jpg)
Chromosomal Anomalies
Trisomy: the presence of an extra chromosome Monosomy: the absence of a whole chromosome
Deletion: the absence of a part of a chromosome
Inversion: the 180° rotation of a part of a chromosome
Translocation: the breakage and rejoining of parts of
two, non-homologous chromosomes
HBD/CA
![Page 106: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/106.jpg)
Chromosomal Abnormalities among Spontaneous Abortions
Type % (n=287)45,XO 23.7Other sex aneuploids 1.0Autosomal trisomies 49.8Triploids 13.2Tetraploids 4.2Rearrangements
balanced 0.3unbalanced 3.1
Other 4.5
![Page 107: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/107.jpg)
Chromosomal Anomalies
Robertsonian translocation break break
21 21
14 14
14 21 14/21
HBD/CA
![Page 108: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/108.jpg)
Chromosomal Anomalies
Possible Gametes for Trans
carrier 14, 21
14/21 14 21 14/21 21, 14/21
14, 14/21 Translocation carrier 14
21
HBD/CA
![Page 109: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/109.jpg)
Chromosomal Anomalies
Carrier x Normal Offspring
14, 21 14, 21 normal 14/21 14,21 normal carrier
21, 14/21 14,21 translocation Down’s
14, 14/21 14,21 “trisomy” 14 (lethal)
14 14,21 monosomy 21 (lethal)
21 14,21 monosomy 14 (lethal)
HBD/CA
![Page 110: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/110.jpg)
Chromosomal Anomalies
Theoretical risk (omitting lethal conditions):
1/3 normal
1/3 translocation carrier (normal)1/3 Down Syndrome
Actual risk for Down Syndrome:
1/10 if female is translocation carrier
1/20 if male is translocation carrier
HBD/CA
![Page 111: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/111.jpg)
Chromosomal Anomalies
Abnormal number/kind of chromosomes
Autosomal anomalies Sex chromosome anomalies
HBD/CA
![Page 112: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/112.jpg)
Autosomal Anomalies
General features:Mental retardation (MR)
Growth retardation (GR)Multiple congenital anomaliesPoor to moderate viabilityPrenatally diagnosableAssociated with spontaneous abortion
(Sab)
HBD/CA/Auto
![Page 113: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/113.jpg)
Autosomal Anomalies
Trisomy 13 - Patau Syndrome Trisomy 18 - Edward Syndrome Trisomy 21 - Down Syndrome 5p- deletion - Cri-du-chat Syndrome
HBD/CA/Auto
![Page 114: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/114.jpg)
Autosomal Abnormalities
![Page 115: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/115.jpg)
Trisomy 21Down Syndrome
![Page 116: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/116.jpg)
Down Syndrome 47,XY,+21
![Page 117: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/117.jpg)
Nomenclature
47, XX, 21+ Female with Down Syndrome
47, XY, 21+Male with Down Syndrome
![Page 118: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/118.jpg)
Trisomy 21 Major Clinical Features
mental retardation slanted palpebral
fissures epicanthal folds small, round, flat
face small mouth,
protruding tongue congenital heart
problems
Brushfield spots (iris) small, hypoplastic
ears simian creases hypotonia, lax joints,
hyperextensive
![Page 119: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/119.jpg)
45, XY, D- G-, t(DqGq)
![Page 120: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/120.jpg)
46, XY, D-, t(DqGq)
![Page 121: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/121.jpg)
Trisomy 13Patau Syndrome
![Page 122: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/122.jpg)
Patau Syndrome 47,XY,13+
![Page 123: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/123.jpg)
Trisomy 13 Major Clinical Features
mental retardation growth retardation microcephaly cleft lip/palate small jaw
(micrognathia) deformed, low-set
ears
polydactyly congenital heart
defects rocker bottom feet seizures low birth weight
![Page 124: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/124.jpg)
Trisomy 18Edward’ Syndrome
![Page 125: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/125.jpg)
Edward’ Syndrome 47,XX,+18
![Page 126: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/126.jpg)
Trisomy 18 Major Clinical Features
mental retardation growth retardation short neck cleft lip/palate dislocated
hips/abnormal pelvis deformed, low-set ears
hypertonia congenital heart
disease horseshoe kidneys hydronephrosis short sternum pyloric stenosis
![Page 127: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/127.jpg)
Cri du chat Syndrome(5p-)
![Page 128: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/128.jpg)
Cri du Chat 5p-
![Page 129: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/129.jpg)
Cri du chat Major Clinical Features
distinctive cat-like cry profound developmental
retardation severe mental
retardation microcephaly hypotonia
hypertelorism congenital heart disease round, moon-shaped face large mouth, short philtrum low set ears hand and foot abnormalities
![Page 130: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/130.jpg)
Sex ChromosomeAbnormalities
![Page 131: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/131.jpg)
Sex Chromosome Anomalies
General features:Some growth retardation (GR)
Reproductive anomalies/problemsGood viabilityPrenatally diagnosableAssociated with spontaneous abortion
(Sab)
HBD/CA/Sex
![Page 132: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/132.jpg)
Sex Chromosome Anomalies
Monosomy X: Turner’s Syndrome (45, X) Trisomy X: Triplo-X Syndrome (47, XXX) Trisomy (47, XXY): Klinefelter’s
Syndrome Trisomy (47, XYY): XYY Syndrome
HBD/CA/Sex
![Page 133: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/133.jpg)
Turner’s Syndrome
![Page 134: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/134.jpg)
Turner’s Syndrome 45,X
![Page 135: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/135.jpg)
Turner’s Syndrome Major Clinical Features
female phenotype short (less than 5 feet) primary amenorrhea low estrogen levels maldevelopment of the
ovaries sterility
webbing of the skin of the neck
wide-spaced nipples edema at birth cardiovascular
problems
![Page 136: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/136.jpg)
Klinefelter’s Syndrome
![Page 137: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/137.jpg)
Klinefelter’s Syndrome 47,XXY
![Page 138: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/138.jpg)
Klinefelter’s Syndrome Major Clinical Features
small testes aspermia (little to no sperm production) gynecomastia long limbs large hands & feet retardation in some fertility in some social limitations in some
![Page 139: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/139.jpg)
Chromosome Instability Syndromes
![Page 140: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/140.jpg)
Bloom’s Syndrome
![Page 141: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/141.jpg)
Bloom’s Syndrome Major Clinical Features
prenatal onset of growth deficiency
short stature malar hypoplasia telangiectatic
erythema of the face mild microcephaly
mild mental deficiency (occasional)
sensitivity to light increased rate of
chromosome breakage
predisposition to malignancy
![Page 142: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/142.jpg)
Fanconi’s Anemia
![Page 143: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/143.jpg)
Fanconi’s Anemia Major Clinical Features
short stature radial hypoplasia hyperpigmentation pancytopenia absent thumbs
progressive muscular wasting
hypoplastic and/or malformed kidneys
congenital dislocation of the hip
![Page 144: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/144.jpg)
Heritable Birth DefectsHeritable Birth Defects
Single Gene DefectsChromosomal Abnormalities
Multifactorial DisordersNon-classical DisordersCancer Genetics
![Page 145: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/145.jpg)
Risk to Relatives for Same Malformation as Index Case
Malformation Risk (population risk compared to degree of relationship)
Pop First Second Third
Cleft lip/palate 1/1000 35x 7x 3xCongenital dislocation/hip 1/1000 40x 4x 1.5xPyloric stenosis 1/1000 20x 5x 2xClubfoot 1/1000 20x 5x 2xAnencephaly/spina bifida 1/500 8x 2x
![Page 146: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/146.jpg)
Multifactorial Inheritance
One trait
Multifactorial: many “factors” governing 1 trait genes plus environment
Polygenic: many loci more than 2 alleles/locus
HBD/MF
![Page 147: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/147.jpg)
Multifactorial Inheritance
environment
PotentialActual
GenotypePhenotype(genes) (appearance)
HBD/MF
![Page 148: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/148.jpg)
Multifactorial Inheritance
anencephaly atopic allergies cleft lip/palate club foot congenital heart disease congential hip dysplasia congenital scoliosis diabetes mellitus epilepsy
hydrocephalus hyperlipidemias manic depressive psychoses non-specific MR NTD presenile dementias pyloric stenosis schizophrenia urinary tract malformations
HBD/MF
![Page 149: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/149.jpg)
Cleft lip/Palate
![Page 150: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/150.jpg)
Cleft lip/Palate Major Clinical Features
failure of upper lip fusion failure of closure of palate defects in tooth development mild ocular hypertelorism (in some) normal intelligence potential for poor speech potential otitis media
![Page 151: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/151.jpg)
Midline Dysplasia
![Page 152: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/152.jpg)
Midline Dysplasia Major Clinical Features
ocular hypertelorism lateral displacement of inner canthi widow’s peak failure of apposition of eyes broad nasal bridge median cleft lip potential bifid nostrils
![Page 153: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/153.jpg)
Neural Tube Defects (NTD)
![Page 154: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/154.jpg)
Neural Tube Defects
anencephaly myelomeningocoele meningocoele encephalocoele
![Page 155: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/155.jpg)
Anencephaly Major Clinical Features
partial or complete absence of calvarium and cranial vault
missing cerebral hemispheres incompatible with postnatal life
![Page 156: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/156.jpg)
Encephalocoele Major Clinical Features
herniation of brain and meninges through a defect in the skull
![Page 157: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/157.jpg)
Spina Bifida Major Clinical Features
defect in spinal cord with sac-like protrusion open or closed wide variability dependent upon location
along spine prognosis based on tissue in sac:
Myelomeningocoele: includes meninges, spinal cord, and nerves
Meningocoele: includes meninges and is covered
![Page 158: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/158.jpg)
Infant of Diabetic Mother
![Page 159: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/159.jpg)
Infant of Diabetic Mother Major Clinical Features
increased intrauterine growth macrosomia (birth weight > 10 lbs.) increased risk for congenital malformations:
caudal regression sacral agenesis hypoplastic femurs renal anomalies cardiac anomalies NTD
![Page 160: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/160.jpg)
Hypospadias Glandis
![Page 161: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/161.jpg)
Hypospadias Glandis Major Clinical Features
opening of the male urethra on the undersurface of the penis
cutaneous or fibrous chordee complications may include:
microphallus cryptorchidism inguinal hernia bifid scrotum
![Page 162: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/162.jpg)
Exstrophy of Bladder(ectopia vesicae)
![Page 163: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/163.jpg)
Exstrophy of Bladder Major Clinical Features
increased MSAFP levels breakdown in cloacal membrane displacement of the bladder exposure of posterior bladder wall increased risk of infection intestinal epithelium between hemibladders phallic separation with epispadias rudimentary hindgut with imperforate anus
![Page 164: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/164.jpg)
Gastroschisis
![Page 165: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/165.jpg)
Gastroschisis Major Clinical Features
increased MSAFP levels intact umbilicus fissure in abdominal wall herniation of abdominal region no sac covering the anomaly increased risk of infection low birth weight small abdominal cavity
![Page 166: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/166.jpg)
Omphalocoele
![Page 167: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/167.jpg)
Omphalocoele Major Clinical Features
increased MSAFP levels herniation of abdominal region including
umbilicus sac covering the anomaly increased risk of infection low birth weight small abdominal cavity
![Page 168: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/168.jpg)
Sirenomelia
![Page 169: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/169.jpg)
Sirenomelia Major Clinical Features
alteration in early vascular development
absent or incomplete development of caudal structures
single lower extremity with posterior alignment of knees and feet
vertebral defects imperforate anus absence of rectum absence of internal &
external genitalia renal agenesis absence of bladder absence of sacrum
![Page 170: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/170.jpg)
Cystic Hygroma
![Page 171: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/171.jpg)
Cystic Hygroma Major Clinical Features
fluid filled, rapidly growing sac or bursa lymphatic in origin located primarily in neck; may be in thorax benign and asymptomatic complications include hemorrhage, infection,
airway obstruction
![Page 172: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/172.jpg)
Rubenstein-Taybi Syndrome
![Page 173: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/173.jpg)
Rubenstein-Taybi Syndrome Major Clinical Features
short stature mental retardation EEG abnormality epicanthal folds hypoplastic maxilla
with narrow palate
low-set/malformed ears hand and foot
anomalies cryptorchidism cardiac murmurs renal anomalies small head
![Page 174: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/174.jpg)
Cornelia de Lange Syndrome
![Page 175: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/175.jpg)
Cornelia de Lange Syndrome Major Clinical Features
short stature mental retardation hypertonicity low-pitched, weak,
growling cry microbrachycephaly bushy eyebrows
small nose high arched palate micrognathia hirsutism hypoplastic nipples and
umbilicus hand and foot
anomalies
![Page 176: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/176.jpg)
Amniotic Band Syndrome
![Page 177: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/177.jpg)
Amniotic Band Syndrome Major Clinical Features
3 weeks: anencephaly facial distortion facial clefting eye defects encephalocoele
5 weeks: cleft lip choanal atresia limb reduction abdominal wall defects thoracic wall defects
7 weeks: cleft palate ear deformation craniostenosis amputation hypoplasia dislocation of hip
![Page 178: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/178.jpg)
Heritable Birth DefectsHeritable Birth Defects
Single Gene Defects Chromosomal Abnormalities
Multifactorial Disorders Non-classical Disorders
Cancer Genetics
![Page 179: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/179.jpg)
Non-Classical Inheritance
Uniparental Disomy (UPD)Trinucleotide Repeat Disorders
(TNR)Mitochondrial/Maternal Inheritance
![Page 180: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/180.jpg)
Uniparental Disomy(UPD)
![Page 181: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/181.jpg)
Uniparental disomy (UPD)
Uniparental disomy: both homologues come from the same parent, none from the other
eg: 2 #7 chromosomes from mom, none from dad
Isodisomy vs heterodisomy
HBD/NCI/UPD
![Page 182: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/182.jpg)
Uniparental disomy (UPD)
female male
7A 7B 7C 7D
Isodisomy 7A 7A
Heterodisomy 7A 7B
HBD/NCI/UPD
![Page 183: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/183.jpg)
Uniparental disomy (UPD)
Prader-Willi and Angelman Syndromes etiologies: autosomal recessive
15q11-13 deletion: PWS results from paternal deletion AS results from maternal deletion
UPD: PWS results from 2 maternal #15 chromosomes AS results from 2 paternal #15 chromosomes
HBD/NCI/UPD
![Page 184: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/184.jpg)
Uniparental disomy (UPD)
Why does it make a difference if an individual has two maternal homologues or two paternal homologues or one homologue fromm each?
HBD/NCI/UPD
![Page 185: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/185.jpg)
Uniparental disomy (UPD)
Genetic Imprinting:
“…modifications of genetic material that take place depending upon whether the information is derived from the mother or the father…” Judith Hall (1990)
chromosomes are “imprinted” by the parent
HBD/NCI/UPD
![Page 186: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/186.jpg)
Uniparental disomy (UPD)
Early mouse experiments
Enucleate an egg cell leaving only cytoplasm
Add 2 maternal genomes (diploid female cell)
OR
Add 2 paternal genomes (diploid male cell)
HBD/NCI/UPD
Control 2 maternal genomes
2 paternal genomes
YS
E
EEM
![Page 187: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/187.jpg)
Prader-Willi Syndrome(Chromosomal)
![Page 188: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/188.jpg)
Prader-Willi Major Clinical Features
mental retardation obesity dental caries macrophagy skin lesions
small hands/feet cryptorchidism small genitalia 15q11-q13 deletion
(70% paternal)
![Page 189: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/189.jpg)
Angelman Syndrome(Chromosomal)
![Page 190: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/190.jpg)
Angelman Major Clinical Features
severe to profound mental retardation inappropriate, excessive laughter epilepsy aphasia 15q11-q13 deletion (80% maternal)
![Page 191: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/191.jpg)
Trinucleotide Repeat(TNR) Disorders
![Page 192: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/192.jpg)
Trinucleotide Repeat Disorders
TNR: repeat of 3 (tri) nucleotides from
30 to 100s of copies (eg: CGGCGGCGGCGGCGGCGG)
premutation: 50 - 230 repeats full mutation: > 230 repeats
HBD/NCI/TNR
![Page 193: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/193.jpg)
Trinucleotide Repeat Disorders
Dynamic mutations: “…the capability of a trinucleotide to
expand into multiple copies within one generation… the ability to increase in copy number over several generations…”
heritable, unstable DNA
HBD/NCI/TNR
![Page 194: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/194.jpg)
Trinucleotide Repeat Disorders
Anticipation: the observation that a disease becomes
progressively worse and demonstrates earlier onset in subsequent generations;
maybe due to or related to dynamic mutations and TNR
HBD/NCI/TNR
![Page 195: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/195.jpg)
Trinucleotide Repeat Disorders
Huntington’s Disease Fragile X Syndrome Myotonic dystrophy Kennedy Disease Spinocerebellar ataxia Machado-Joseph disease
HBD/NCI/TNR
![Page 196: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/196.jpg)
Myotonic Dystrophy(AD)
![Page 197: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/197.jpg)
Myotonic Dystrophy Major Clinical Features
Fetus: oligohydramnios decreased movement impaired fetal swallowing
Newborn: profound neonatal hypotonia severe feeding problems
Adult: myotonia muscle weakness and wasting cataracts GI, cardiac, endocrine problems 50-100 TNR = affected
![Page 198: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/198.jpg)
Huntington’s Chorea(AD)
![Page 199: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/199.jpg)
Huntington’s Chorea Major Clinical Features
chorea dementia clumsy gait indistinct speech
emotional instability paranoia progressive
deterioration late onset of symptoms
![Page 200: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/200.jpg)
Fragile X Syndrome(Martin-Bell Syndrome)
(Chromosomal)
![Page 201: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/201.jpg)
Fragile X Major Clinical Features
Males: large loppy ears prominent forehead
and jaw large testes educable to severe
MR 20% unaffected,
transmitting males
Females: slow learners mild MR shy some affected carriers
![Page 202: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/202.jpg)
Fragile X Syndrome
![Page 203: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/203.jpg)
![Page 204: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/204.jpg)
Fragile X
![Page 205: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/205.jpg)
Mitochondrial/Maternal Inheritance
![Page 206: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/206.jpg)
Mitochondrial Inheritance
Mitochondria: semi-autonomous, circular, naked DNA (~prokaryotic
chromosome) encodes tRNA genes, rRNA genes, some structural genes
(mRNA) important in respiration, production of ATP critical to tissues with high demand for ATP “maternally” inherited random segregation during cell division = heteroplasmy higher mutation rate than nuclear DNA
HBD/NCI/Mito
![Page 207: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/207.jpg)
Mitochondrial Inheritance
Heteroplasmy = different % of normal & abnormal mitochondria in single cells or tissues
and or and
HBD/NCI/Mito
x x x x x x o o o o o o o o o o o o
O o o
x x x xo o o o o
x x o o o o o o o
x o o o o o o o o o
x x x x xo o o
![Page 208: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/208.jpg)
Mitochondrial Inheritance
Disease phenotype dependent upon:
gene(s) involved type of mutation (missense/nonsense/deletion) % normal vs abnormal mitochondria tissue involved
HBD/NCI/Mito
![Page 209: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/209.jpg)
Mitochondrial Disorders
Diabetes with sensorineural deafness HOCM (hypertrophic cardiomyopathy with myopathy)
Leber’s Hereditary Optic Neuropathy MELAS (encephalopathy, lactic acidosis, stroke-like episodes)
MERRF (myoclonic epilepsy, mito myopathy with ragged-red fibers)
HBD/NCI/MD
![Page 210: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/210.jpg)
Myoclonic Encephalopathy with Ragged Red Fibers
(MERRF)
![Page 211: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/211.jpg)
MERRF Major Clinical Features
ataxia epilepsy hypotonia muscle weakness lactic acidemia ragged red fibers seen in muscle biopsy abnormal energy metabolism in muscles
![Page 212: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/212.jpg)
![Page 213: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/213.jpg)
Heritable Birth DefectsHeritable Birth Defects
Single Gene DefectsChromosomal AbnormalitiesMultifactorial DisordersNon-classical Disorders
Cancer Genetics
![Page 214: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/214.jpg)
Basic Definitions of Terms
Proto-oncogene = a normal gene which controls cell division (“speeds up”)
Oncogene = a mutated or abnormal proto-oncogene which induces cell division at the wrong time, place or rate
Tumor Suppressor (TS) gene = a normal gene which controls cell division (“slows down”)
Mutated TS gene = an abnormal gene which fails to stop cell division at the appropriate time or place
![Page 215: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/215.jpg)
General Classes of Cancer
Breast Colorectal Leukemia Lymphoma Skin
Ovarian Pancreatic Prostate Testicular Uterine
HBD/CG
![Page 216: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/216.jpg)
Specific Cancers
CML, AML (leukemias) Burkitt’s, Hodgkin’s, non-Hodgkin’s (lymphomas) Retinoblastoma (retina) LiFraumeni Syndrome
![Page 217: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/217.jpg)
Retinoblastoma(AD)
![Page 218: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/218.jpg)
Retinoblastoma Major Clinical Features
malignant tumor of the retina onset at birth/early childhood bilateral cases are hereditary poor vision or blindness painful, red eye 13q14 deletion
![Page 219: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/219.jpg)
Chronic Myelogenous Leukemia (CML)
![Page 220: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/220.jpg)
CML Major Clinical Features
hyperplastic bone marrow granulocytic leukocytosis weakness due to anemia pain due to splenomegaly weight loss Philadelphia chromosome = 9/22 translocation 9q34 abl gene + 22q11 bcr gene hybrid gene forms new hybrid protein
![Page 221: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/221.jpg)
46,XX,Ph1+
![Page 222: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/222.jpg)
Non-Heritable Birth DefectsNon-Heritable Birth Defects
Environmental Teratogens
![Page 223: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/223.jpg)
“Non-Heritable” Birth Defects (NHBD)
teratogen = any chemical, biological or physical agent that increases the probability of a birth defect
![Page 224: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/224.jpg)
“Non-Heritable” Birth Defects
drugs (OTC/illegal)
chemicals X-rays oxygen
deprivation toxins
infections accidents/injuries alcohol nicotine caffeine poisons
![Page 225: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/225.jpg)
Fetal Alcohol Syndrome
![Page 226: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/226.jpg)
Fetal Alcohol Syndrome Major Clinical Features
prenatal growth deficiency
thin upper lips mental retardation visual impairment hearing loss low nasal bridge epicanthal folds
indistinct philtrum short palpebral fissures flat midface short nose micrognathia malformations of the
heart, kidney, eye, brain, ear, skeleton
![Page 227: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/227.jpg)
Fetal Rubella Effects
![Page 228: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/228.jpg)
Fetal Rubella Effects Major Clinical Features
deafness cataracts patent ductus arteriosus mental retardation glaucoma
septal defects thrombocytopenia hepatosplenomegaly interstitial pneumonia
![Page 229: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/229.jpg)
Fetal Hydantoin Syndrome
![Page 230: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/230.jpg)
Fetal Hydantoin Major Clinical Features
mental retardation distal phalangeal hypoplasia facial clefts cardiac anomalies
![Page 231: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/231.jpg)
Fetal Warfarin Effects
![Page 232: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/232.jpg)
Fetal Warfarin Effects Major Clinical Features
nasal hypoplasia depressed nasal bridge skeletal stippling mild hypoplasia of nails short fingers low birth weight mental retardation
![Page 233: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/233.jpg)
Hyperthermia
![Page 234: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/234.jpg)
Hyperthermia Major Clinical Features
defects dependent upon time of exposure
mental deficiency hypertonicity neurogenic contractures seizures hormone deficiency
microphthalmia micrognathia midfacial hypoplasia external ear anomalies cleft lip/palate microcephaly
![Page 235: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/235.jpg)
Pierre-Robin Syndrome
![Page 236: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/236.jpg)
Pierre-Robin Syndrome Major Clinical Features
micrognathia glossoptosis cleft soft palate early mandibular hypoplasia upper respiratory obstruction failure to thrive
![Page 237: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/237.jpg)
Potter’s Syndrome
![Page 238: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/238.jpg)
Potter’s Syndrome Major Clinical Features
renal agenesis oligohydramnios multiple malformations growth deficiency fetal compression in utero altered facies limb positioning defects
![Page 239: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/239.jpg)
Amelia/Phocomelia
![Page 240: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/240.jpg)
Amelia/Phocomelia Major Clinical Features
Amelia: complete absence of limb/limbs
Phocomelia: microbrachycephaly mild to severe mental deficiency growth deficiency cleft lip and/or cleft palate sparse hair cryptorchidism
![Page 241: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/241.jpg)
Radiation Exposure
![Page 242: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/242.jpg)
Radiation Exposure Major Clinical Features
defects dependent upon dosage and time high dose:
lethal early in pregnancy multiple malformations if later in pregnancy
2-10 rads: very slight increased risk for birth defects if
between 2 and 4 weeks gestation 2 rads:
very low increased risk
![Page 243: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/243.jpg)
Caffeine/Tobacco(“stimulants”)
![Page 244: Comprehensive survey of human genetic diseases](https://reader035.fdocuments.us/reader035/viewer/2022081418/554b3359b4c905a2058b50a7/html5/thumbnails/244.jpg)
Caffeine/Tobacco Major Clinical Features
caffeine: potential co-teratogen with tobacco
tobacco: miscarriages reduced birth weight due to vasoconstriction potential co-teratogen with caffeine