Genetic Diseases

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A great overview of genetic disorders

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Medical Genetics:

Medical Genetics Biology 3327

Overview:

Overview

Importance of Genetics to Medicine:

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

Importance of Genetics to Medicine:

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

Importance of Genetics to Medicine:

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

Terms & Definitions:

Terms & Definitions birth defect genetic disorder malformation deformation disruption sequence syndrome association morphology dysmorphology variability heterogeneity pleiotrophy organogenesis morphogenesis hyperplasia hypoplasia dysplasia

Pedigree Symbols:

Pedigree Symbols See text for additional symbols: normal male/female deceased unknown sex stillbirth affected male/female miscarriage (Sab) marriage/mating line termination of pregnancy (Tab) illegitimacy line pregnancy consanguineous mating consultand identical/fraternal twins proband

Modes of Inheritance & Selected Examples:

Modes of Inheritance & Selected Examples

Heritable Birth Defects (HBD):

Heritable Birth Defects (HBD) Single Gene Defects (SGD) Chromosomal Anomalies (CA) Multifactorial Inheritance (MF) Non-Classical Inheritance (NCI) Cancer Genetics (CG)

“Non-Heritable” Birth Defects (NHBD):

“Non-Heritable” Birth Defects (NHBD) Environmental teratogens teratogen = any chemical, biological or physical agent that increases the probability of a birth defect

Heritable Birth Defects (HBD):

Heritable Birth Defects (HBD) Single Gene Defects Chromosomal Abnormalities Multifactorial Disorders Non-classical Disorders Cancer Genetics

Single Gene Defects:

Single Gene Defects Autosomal recessive Autosomal dominant X-linked recessive X-linked dominant HBD

Autosomal recessive (AR):

Autosomal recessive (AR) One trait, 2 alleles A = dominant normal allele a = recessive abnormal allele Homozygous dominant = normal (AA) Heterozygous dominant = normal, carrier (Aa) Homozygous recessive = affected (aa ) HBD/SGD/AR

Autosomal recessive:

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

AR Pedigree:

AR Pedigree Pedigree symbols Proband “Horizontal” Equal numbers of males and females Phenotypically normal parents 25% recurrence risk HBD/SGD/AR

AR Disorders :

AR Disorders PKU - phenylketonuria Galactosemia Homocystinuria Cystic fibrosis Tay-Sachs Sickle cell anemia HBD/SGD/AR

AR Disorders & Ethnicity:

AR Disorders & Ethnicity Cystic fibrosis Tay-Sachs Sickle cell anemia Thalassemia Caucasians Ashkenazai Jews African Americans Mediterraneans (ex:Greeks/Italians ) HBD/SGD/AR

Inborn Errors of Metabolism:

Inborn Errors of Metabolism Phenylpyruvic acid 1 Phenylalanine DOPA DOPA Quinone 2 3 Tyrosine P-hydroxyphenylpyruvic acid Homogentisic acid 4 Thyroid Hormone Maleylacetoacetic acid 1 = tyrosinase/albinism 3 = tyrosinase/albinism 2 = phenylalanine hydroxylase/PKU 4 = homogentisic acid oxidase/alcaptonuria HBD/SGD/AR

Inborn Errors of Metabolism General Characteristics:

Inborn 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

PowerPoint Presentation:

Phenylketonuria PKU

PKU Major Clinical Features:

PKU Major Clinical Features MR Agitated behavior EEG abnormalities hyperactive reflexes muscular hypertonicity inability to talk inability to walk tremors seizures

PowerPoint Presentation:

Tay-Sachs Disease

Tay-Sachs Major Clinical Features:

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)

PowerPoint Presentation:

Cystic Fibrosis

CF Major Clinical Features:

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

CFTR Gene (Cystic Fibrosis Transmembrane Regulator):

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

PowerPoint Presentation:

Niemann-Pick Disease

NP Major Clinical Features:

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

PowerPoint Presentation:

Mucopolysaccharidoses MPS

MPS General Clinical Features:

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

PowerPoint Presentation:

Hurler’s Syndrome MPS Type 1

Hurler Major Clinical Features:

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

PowerPoint Presentation:

Sanfilippo Syndrome MPS Type 111

Sanfilippo Major Clinical Features:

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

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Scheie’s Syndrome MPS Type V

Scheie’s Major Clinical Features:

Scheie’s Major Clinical Features normal intelligence corneal clouding joint limitation in hands aortic valvular defect body hirsutism hernias broad hands and feet

PowerPoint Presentation:

von Gierke’s Disease (Glycogen Storage Disorder Type I)

Von Gierke’s Major Clinical Features:

Von Gierke’s Major Clinical Features absence of liver glucose–6-phosphatase hypoglycemia short stature good prognosis accumulation of glycogen in liver and kidneys

PowerPoint Presentation:

Ehlers-Danlos Syndrome

Ehlers-Danlos Major Clinical Features:

Ehlers-Danlos Major Clinical Features hypermobile “lop” ears velvety skin fragile hyperextensive skin hyperextensible joints easy to bruise mitral valve prolapse collagen defect

PowerPoint Presentation:

Progeria

Progeria Major Clinical Features:

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

PowerPoint Presentation:

Spinal Muscular Atrophy Type I (Werdnig-Hoffman Disease)

SMA Type I Clinical Features:

SMA Type I Clinical Features hypotonia weakness decreased or absent deep tendon reflexes pulmonary infection respiratory failure rapid coarse to death at early age

PowerPoint Presentation:

Homocystinuria

Homocystinuria Clinical Features:

Homocystinuria Clinical Features abnormalities of skeletal system genu valgum scoliosis kyphosis pectus excavatum osteoporosis restricted joint mobility ectopia lentis (downward) thrombosis mental retardation

Single Gene Defects:

Single Gene Defects Autosomal recessive Autosomal dominant X-linked recessive X-linked dominant

Autosomal dominant (AD):

Autosomal dominant (AD) One Trait, 2 alleles A = dominant abnormal allele a = recessive normal allele Homozygous dominant = affected, often lethal (AA) Heterozygous dominant = affected (Aa) Homozygous recessive = normal (aa) HBD/SGD/AD

Autosomal Dominant (AD) :

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

AD Pedigree:

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

AD Disorders:

AD Disorders Marfan’s Syndrome Huntington’s Chorea Osteogenesis imperfecta Neurofibromatosis Retinoblastoma Tuberous sclerosis Apert’s Syndrome Multiple polyposis of colon HBD/SGD/AD

PowerPoint Presentation:

Marfan Syndrome

Marfan Clinical Features:

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

PowerPoint Presentation:

Crouzon’s Syndrome

Crouzon Major Clinical Features:

Crouzon Major Clinical Features shallow orbits premature craniosynostosis maxillary hypoplasia frontal bossing conductive hearing loss mental retardation (occasional) seizures (occasional)

PowerPoint Presentation:

Apert’s Syndrome

Apert Major Clinical Features:

Apert Major Clinical Features mental deficiency occasional normal intelligence irregular craniosynostosis (“Tower” skull) midfacial hypoplasia syndactyly (“mitten hand”) hypertelorism strabismus small nose maxillary hypoplasia

PowerPoint Presentation:

Treacher-Collin’s Syndrome

Treacher-Collin Clinical Features:

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

PowerPoint Presentation:

Cherubism

Cherubism Major Clinical Features:

Cherubism Major Clinical Features tumor-like facial changes benign dysplasia of jaw bone serious dental anomalies

PowerPoint Presentation:

Neurofibromatosis

Neurofibromatosis Major Clinical Features:

Neurofibromatosis Major Clinical Features neurofibromas of skin, CNS, eye, stomach, liver, intestine, kidney, bladder, larynx “café-au-lait” spots kyphoscoliosis feeble-minded (occasional) abnormal pigmentation of skin iris hamartomas (Lisch nodules) tumorous partial giantism (occasional)

PowerPoint Presentation:

Achondroplastic Dwarfism

Achondroplastic Dwarfism Major Clinical Features:

Achondroplastic Dwarfism Major Clinical Features megalocephaly short limbs low nasal bridge caudal narrowing of spinal cord lumbar lordosis skeletal anomalies mild hypotonia normal intelligence

PowerPoint Presentation:

Osteogenesis Imperfecta

Osteogenesis Imperfecta Major Clinical Features:

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

PowerPoint Presentation:

Holt-Oram Syndrome

Holt-Oram Major Clinical Features:

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

Single Gene Defects:

Single Gene Defects Autosomal recessive Autosomal dominant X-linked recessive X-linked dominant

X-linked recessive (XR):

X-linked recessive (XR) One trait, 2 alleles A = dominant normal allele a = recessive abnormal allele Must consider which parent has the abnormal gene when assessing risk HBD/SGD/XR

X-linked recessive (XR):

X-linked recessive (XR) Homozygous dominant = normal female (X A X A ) Heterozygous dominant = normal female carrier (X A X a ) Homozygous recessive = affected female (X a X a ) Hemizygous dominant = normal male (X A Y) Hemizygous recessive = affected male (X a Y) HBD/SGD/XR

X-linked recessive (XR):

X-linked recessive (XR) Heterozygous normal mother (carrier) Hemizygous normal father 50% risk for an affected male 50% 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

XR Pedigree:

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

XR Pedigree:

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

XR Disorders:

XR Disorders Duchenne’s Muscular Dystrophy Hemophilia Hunter’s Syndrome Aarskog’s Syndrome Lesch-Nyhan Syndrome Pyruvate dehydrogenase deficiency HBD/SGD/XR

PowerPoint Presentation:

Muscular Dystrophy

Muscular Dystrophy Major Clinical Features:

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

PowerPoint Presentation:

Aarskog Syndrome

Aarskog Major Clinical Features:

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

PowerPoint Presentation:

Lesch-Nyhan Syndrome

Lesch-Nyhan Major Clinical Features:

Lesch-Nyhan Major Clinical Features spasticity choreoathetosis self-mutilation autistic behavior growth deficiency gout HGPRT deficiency (enzyme of purine metabolism)

PowerPoint Presentation:

Hunter Syndrome (MPS Type II)

Hunter Major Clinical Features:

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

PowerPoint Presentation:

Bruton’s Agammaglobulinemia

Bruton Major Clinical Features:

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

Single Gene Defects:

Single Gene Defects Autosomal recessive Autosomal dominant X-linked recessive X-linked dominant

X-linked dominant (XD):

X-linked dominant (XD) One trait, 2 alleles A = dominant abnormal allele a = recessive normal allele Must consider which parent has the abnormal gene when assessing risk HBD/SGD/XD

X-linked dominant (XD):

X-linked dominant (XD) Homozygous dominant = affected female (X A X A ) Heterozygous dominant = affected female (X A X a ) Homozygous recessive = normal female (X a X a ) Hemizygous dominant = affected male (X A Y) Hemizygous recessive = normal male (X a Y) HBD/SGD/XD

X-Linked Dominant (XD):

X-Linked Dominant (XD) For heterozygous affected females: 50% risk for affected son 50% risk for affected daughter For hemizygous affected males: 100% risk for affected daughter 0% 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

XD Pedigree:

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

XD Disorders:

XD Disorders Vitamin D resistant rickets Browning of the enamel of the teeth Albright’s hereditary osteodystrophy Taybi Syndrome HBD/SGD/XD

PowerPoint Presentation:

Vitamin D-resistant Rickets with hypophosphatemia

Resistant Rickets Major Clinical Features:

Resistant Rickets Major Clinical Features bone deficiencies (“bowed” legs) dental anomalies decreased phosphate in serum short stature normal intelligence

Heritable Birth Defects:

Heritable Birth Defects Single Gene Defects Chromosomal Abnormalities Multifactorial Disorders Non-classical Disorders Cancer Genetics

Populations at Risk for Chromosome Errors:

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 CML Bloom’s Syndrome Burkitt’s lymphoma Fanconi’s anemia Neurofibromatosis Xeroderma pigmentosum Retinoblastoma Familial adenomatous polyposis Gardner’s Syndrome Bruton’s agammaglobulinemia Wiskott-Aldrich Syndrome

Chromosome Preparation & Analysis:

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

Chromosome Banding :

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)

Chromosomes: A Review:

Chromosomes: A Review Homologous pairs Autosomes/sex chromosomes Karyotype: arrange by size Centromere position: metacentric submetacentric/p/q acrocentric/satellites/rDNA G Banding Nomenclature HBD/CA

Normal Female: 46,XX:

Normal Female: 46,XX

Normal Male: 46,XY:

Normal Male: 46,XY

Chromosomes: A Review:

Acrocentric chromosome having a “bad hair day” Note chromatids “Fibrous” appearance No bands apparent Chromosomes: A Review HBD/CA

Chromosomes: A Review:

Chromosomes: A Review Idiogram: standard for bands p and q arms centromere position bands numbered satellited chromosomes HBD/CA

Chromosomes: A Review:

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 3 4

Chromosomal Anomalies:

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

Chromosomal Abnormalities among Spontaneous Abortions:

Chromosomal Abnormalities among Spontaneous Abortions Type % (n=287) 45,XO 23.7 Other sex aneuploids 1.0 Autosomal trisomies 49.8 Triploids 13.2 Tetraploids 4.2 Rearrangements balanced 0.3 unbalanced 3.1 Other 4.5

Chromosomal Anomalies:

Chromosomal Anomalies Robertsonian translocation break break 21 21 14 14 14 21 14/21 HBD/CA

Chromosomal Anomalies:

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

Chromosomal Anomalies:

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

Chromosomal Anomalies:

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

Chromosomal Anomalies:

Chromosomal Anomalies Abnormal number/kind of chromosomes Autosomal anomalies Sex chromosome anomalies HBD/CA

Autosomal Anomalies:

Autosomal Anomalies General features: Mental retardation (MR) Growth retardation (GR) Multiple congenital anomalies Poor to moderate viability Prenatally diagnosable Associated with spontaneous abortion (Sab) HBD/CA/Auto

Autosomal Anomalies:

Autosomal Anomalies Trisomy 13 - Patau Syndrome Trisomy 18 - Edward Syndrome Trisomy 21 - Down Syndrome 5p - deletion - Cri-du-chat Syndrome HBD/CA/Auto

PowerPoint Presentation:

Autosomal Abnormalities

PowerPoint Presentation:

Trisomy 21 Down Syndrome

Down Syndrome 47,XY,+21:

Down Syndrome 47,XY,+21

Nomenclature:

Nomenclature 47, XX, 21+ Female with Down Syndrome 47, XY, 21+ Male with Down Syndrome

Trisomy 21 Major Clinical Features:

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

PowerPoint Presentation:

45, XY, D- G-, t(DqGq)

46, XY, D-, t(DqGq):

46, XY, D-, t(DqGq)

PowerPoint Presentation:

Trisomy 13 Patau Syndrome

Patau Syndrome 47,XY,13+:

Patau Syndrome 47,XY,13+

Trisomy 13 Major Clinical Features:

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

PowerPoint Presentation:

Trisomy 18 Edward’ Syndrome

Edward’ Syndrome 47,XX,+18:

Edward’ Syndrome 47,XX,+18

Trisomy 18 Major Clinical Features:

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

PowerPoint Presentation:

Cri du chat Syndrome (5p-)

Cri du Chat 5p-:

Cri du Chat 5p-

Cri du chat Major Clinical Features:

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

PowerPoint Presentation:

Sex Chromosome Abnormalities

Sex Chromosome Anomalies:

Sex Chromosome Anomalies General features: Some growth retardation (GR) Reproductive anomalies/problems Good viability Prenatally diagnosable Associated with spontaneous abortion (Sab) HBD/CA/Sex

Sex Chromosome Anomalies:

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

PowerPoint Presentation:

Turner’s Syndrome

Turner’s Syndrome 45,X:

Turner’s Syndrome 45,X

Turner’s Syndrome Major Clinical Features:

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

PowerPoint Presentation:

Klinefelter’s Syndrome

Klinefelter’s Syndrome 47,XXY:

Klinefelter’s Syndrome 47,XXY

Klinefelter’s Syndrome Major Clinical Features:

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

PowerPoint Presentation:

Chromosome Instability Syndromes

PowerPoint Presentation:

Bloom’s Syndrome

Bloom’s Syndrome Major Clinical Features:

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

PowerPoint Presentation:

Fanconi’s Anemia

Fanconi’s Anemia Major Clinical Features:

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

Heritable Birth Defects:

Heritable Birth Defects Single Gene Defects Chromosomal Abnormalities Multifactorial Disorders Non-classical Disorders Cancer Genetics

Risk to Relatives for Same Malformation as Index Case:

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 3x Congenital dislocation/hip 1/1000 40x 4x 1.5x Pyloric stenosis 1/1000 20x 5x 2x Clubfoot 1/1000 20x 5x 2x Anencephaly/spina bifida 1/500 8x 2x

Multifactorial Inheritance:

Multifactorial Inheritance One trait Multifactorial: many “factors” governing 1 trait genes plus environment Polygenic: many loci more than 2 alleles/locus HBD/MF

Multifactorial Inheritance:

Multifactorial Inheritance environment Potential Actual Genotype Phenotype (genes) (appearance) HBD/MF

Multifactorial Inheritance:

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

PowerPoint Presentation:

Cleft lip/Palate

Cleft lip/Palate Major Clinical Features:

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

PowerPoint Presentation:

Midline Dysplasia

Midline Dysplasia Major Clinical Features:

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

PowerPoint Presentation:

Neural Tube Defects (NTD)

Neural Tube Defects :

Neural Tube Defects anencephaly myelomeningocoele meningocoele encephalocoele

Anencephaly Major Clinical Features:

Anencephaly Major Clinical Features partial or complete absence of calvarium and cranial vault missing cerebral hemispheres incompatible with postnatal life

Encephalocoele Major Clinical Features:

Encephalocoele Major Clinical Features herniation of brain and meninges through a defect in the skull

Spina Bifida Major Clinical Features:

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

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Infant of Diabetic Mother

Infant of Diabetic Mother Major Clinical Features:

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

PowerPoint Presentation:

Hypospadias Glandis

Hypospadias Glandis Major Clinical Features:

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

PowerPoint Presentation:

Exstrophy of Bladder (ectopia vesicae)

Exstrophy of Bladder Major Clinical Features:

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

PowerPoint Presentation:

Gastroschisis

Gastroschisis Major Clinical Features:

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

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Omphalocoele

Omphalocoele Major Clinical Features:

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

PowerPoint Presentation:

Sirenomelia

Sirenomelia Major Clinical Features:

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

PowerPoint Presentation:

Cystic Hygroma

Cystic Hygroma Major Clinical Features:

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

PowerPoint Presentation:

Rubenstein-Taybi Syndrome

Rubenstein-Taybi Syndrome Major Clinical Features:

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

PowerPoint Presentation:

Cornelia de Lange Syndrome

Cornelia de Lange Syndrome Major Clinical Features:

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

PowerPoint Presentation:

Amniotic Band Syndrome

Amniotic Band Syndrome Major Clinical Features:

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

Heritable Birth Defects:

Heritable Birth Defects Single Gene Defects Chromosomal Abnormalities Multifactorial Disorders Non-classical Disorders Cancer Genetics

Non-Classical Inheritance:

Non-Classical Inheritance Uniparental Disomy (UPD) Trinucleotide Repeat Disorders (TNR) Mitochondrial/Maternal Inheritance

PowerPoint Presentation:

Uniparental Disomy (UPD)

Uniparental disomy (UPD):

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

Uniparental disomy (UPD):

Uniparental disomy (UPD) female male 7A 7B 7C 7D Isodisomy 7A 7A Heterodisomy 7A 7B HBD/NCI/UPD

Uniparental disomy (UPD):

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

Uniparental disomy (UPD):

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

Uniparental disomy (UPD):

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

Uniparental disomy (UPD):

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

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Prader-Willi Syndrome (Chromosomal)

Prader-Willi Major Clinical Features:

Prader-Willi Major Clinical Features mental retardation obesity dental caries macrophagy skin lesions small hands/feet cryptorchidism small genitalia 15q11-q13 deletion (70% paternal)

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Angelman Syndrome (Chromosomal)

Angelman Major Clinical Features:

Angelman Major Clinical Features severe to profound mental retardation inappropriate, excessive laughter epilepsy aphasia 15q11-q13 deletion (80% maternal)

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Trinucleotide Repeat (TNR) Disorders

Trinucleotide Repeat Disorders:

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

Trinucleotide Repeat Disorders:

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

Trinucleotide Repeat Disorders:

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

Trinucleotide Repeat Disorders:

Trinucleotide Repeat Disorders Huntington’s Disease Fragile X Syndrome Myotonic dystrophy Kennedy Disease Spinocerebellar ataxia Machado-Joseph disease HBD/NCI/TNR

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Myotonic Dystrophy (AD)

Myotonic Dystrophy Major Clinical Features:

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

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Huntington’s Chorea (AD)

Huntington’s Chorea Major Clinical Features:

Huntington’s Chorea Major Clinical Features chorea dementia clumsy gait indistinct speech emotional instability paranoia progressive deterioration late onset of symptoms

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Fragile X Syndrome (Martin-Bell Syndrome) (Chromosomal)

Fragile X Major Clinical Features:

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

Fragile X Syndrome:

Fragile X Syndrome

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Fragile X

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Mitochondrial/Maternal Inheritance

Mitochondrial Inheritance:

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

Mitochondrial Inheritance:

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 x o 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 x o o o

Mitochondrial Inheritance:

Mitochondrial Inheritance Disease phenotype dependent upon: gene(s) involved type of mutation (missense/nonsense/deletion) % normal vs abnormal mitochondria tissue involved HBD/NCI/Mito

Mitochondrial Disorders:

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

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Myoclonic Encephalopathy with Ragged Red Fibers (MERRF)

MERRF Major Clinical Features:

MERRF Major Clinical Features ataxia epilepsy hypotonia muscle weakness lactic acidemia ragged red fibers seen in muscle biopsy abnormal energy metabolism in muscles

Heritable Birth Defects:

Heritable Birth Defects Single Gene Defects Chromosomal Abnormalities Multifactorial Disorders Non-classical Disorders Cancer Genetics

Basic Definitions of Terms:

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

General Classes of Cancer:

General Classes of Cancer Breast Colorectal Leukemia Lymphoma Skin Ovarian Pancreatic Prostate Testicular Uterine HBD/CG

Specific Cancers:

Specific Cancers CML, AML (leukemias) Burkitt’s, Hodgkin’s, non-Hodgkin’s (lymphomas) Retinoblastoma (retina) LiFraumeni Syndrome

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Retinoblastoma (AD)

Retinoblastoma Major Clinical Features:

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

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Chronic Myelogenous Leukemia (CML)

CML Major Clinical Features:

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

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46,XX,Ph1+

Non-Heritable Birth Defects:

Non-Heritable Birth Defects Environmental Teratogens

“Non-Heritable” Birth Defects (NHBD):

“Non-Heritable” Birth Defects ( NHBD) teratogen = any chemical, biological or physical agent that increases the probability of a birth defect

“Non-Heritable” Birth Defects:

“Non-Heritable” Birth Defects drugs (OTC/illegal) chemicals X-rays oxygen deprivation toxins infections accidents/injuries alcohol nicotine caffeine poisons

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Fetal Alcohol Syndrome

Fetal Alcohol Syndrome Major Clinical Features:

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

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Fetal Rubella Effects

Fetal Rubella Effects Major Clinical Features:

Fetal Rubella Effects Major Clinical Features deafness cataracts patent ductus arteriosus mental retardation glaucoma septal defects thrombocytopenia hepatosplenomegaly interstitial pneumonia

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Fetal Hydantoin Syndrome

Fetal Hydantoin Major Clinical Features:

Fetal Hydantoin Major Clinical Features mental retardation distal phalangeal hypoplasia facial clefts cardiac anomalies

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Fetal Warfarin Effects

Fetal Warfarin Effects Major Clinical Features:

Fetal Warfarin Effects Major Clinical Features nasal hypoplasia depressed nasal bridge skeletal stippling mild hypoplasia of nails short fingers low birth weight mental retardation

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Hyperthermia

Hyperthermia Major Clinical Features:

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

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Pierre-Robin Syndrome

Pierre-Robin Syndrome Major Clinical Features:

Pierre-Robin Syndrome Major Clinical Features micrognathia glossoptosis cleft soft palate early mandibular hypoplasia upper respiratory obstruction failure to thrive

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Potter’s Syndrome

Potter’s Syndrome Major Clinical Features:

Potter’s Syndrome Major Clinical Features renal agenesis oligohydramnios multiple malformations growth deficiency fetal compression in utero altered facies limb positioning defects

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Amelia/Phocomelia

Amelia/Phocomelia Major Clinical Features:

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

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Radiation Exposure

Radiation Exposure Major Clinical Features:

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

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Caffeine/Tobacco (“stimulants”)

Caffeine/Tobacco Major Clinical Features:

Caffeine/Tobacco Major Clinical Features caffeine: potential co-teratogen with tobacco tobacco: miscarriages reduced birth weight due to vasoconstriction potential co-teratogen with caffeine

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