Comprehensive survey of human genetic diseases

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Comprehensive survey of human genetic diseases

  1. 1. Medical GeneticsMedical GeneticsFor Medical StudentFor Medical Student
  2. 2. Overview
  3. 3. 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
  4. 4. 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 & clinicalobservation
  5. 5. Importance of Genetics to MedicineTriple theme: genetic traits as they segregate through families allowsinsights into health of the population flow of info from DNA to RNA to protein links geneticsto physiology ethical issues linked to treatment, therapy options,research, decision-making and quality of life
  6. 6. Terms & Definitions birth defect genetic disorder malformation deformation disruption sequence syndrome association morphology dysmorphology variability heterogeneity pleiotrophy organogenesis morphogenesis hyperplasia hypoplasia dysplasia
  7. 7. Pedigree SymbolsSee 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
  8. 8. Modes of Inheritance &Selected Examples
  9. 9. Heritable Birth Defects (HBD) Single Gene Defects (SGD) Chromosomal Anomalies (CA) Multifactorial Inheritance (MF) Non-Classical Inheritance (NCI) Cancer Genetics (CG)
  10. 10. “Non-Heritable” Birth Defects (NHBD) Environmental teratogensteratogen = any chemical, biologicalor physical agent that increases theprobability of a birth defect
  11. 11. Heritable Birth DefectsHeritable Birth Defects(HBD)(HBD) Single Gene DefectsChromosomal AbnormalitiesMultifactorial DisordersNon-classical DisordersCancer Genetics
  12. 12. Single Gene DefectsSingle Gene Defects Autosomal recessiveAutosomal dominantX-linked recessiveX-linked dominantHBD
  13. 13. Autosomal recessive (AR) One trait, 2 allelesA = dominant normal allelea = recessive abnormal alleleHomozygous dominant = normal (AA)Heterozygous dominant = normal, carrier (Aa)Homozygous recessive = affected (aa)HBD/SGD/AR
  14. 14. Autosomal recessive Carrier parents Normal parentalphenotype 75% chance for normaloffspring 25% chance for affectedoffspring Males & females equallyaffected “Inborn errors ofmetabolism” Associated with specificethnic groupsHBD/SGD/AR
  15. 15. AR Pedigree Pedigree symbols Proband “Horizontal” Equal numbers ofmales and females Phenotypically normalparents 25% recurrence riskHBD/SGD/AR
  16. 16. AR Disorders PKU - phenylketonuria Galactosemia Homocystinuria Cystic fibrosis Tay-Sachs Sickle cell anemiaHBD/SGD/AR
  17. 17. AR Disorders & Ethnicity Cystic fibrosis Tay-Sachs Sickle cell anemia Thalassemia Caucasians Ashkenazai Jews African Americans Mediterraneans(ex:Greeks/Italians)HBD/SGD/AR
  18. 18. Inborn Errors of MetabolismPhenylpyruvic acid1Phenylalanine DOPA DOPA Quinone23TyrosineP-hydroxyphenylpyruvic acid Homogentisic acid4Thyroid HormoneMaleylacetoacetic acid1 = tyrosinase/albinism 3 = tyrosinase/albinism2 = phenylalanine hydroxylase/PKU 4 = homogentisic acid oxidase/alcaptonuriaHBD/SGD/AR
  19. 19. Inborn Errors of MetabolismInborn Errors of MetabolismGeneral 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
  20. 20. PhenylketonuriaPKU
  21. 21. PKU Major ClinicalFeatures MR Agitated behavior EEG abnormalities hyperactive reflexes muscular hypertonicity inability to talk inability to walk tremors seizures
  22. 22. Tay-Sachs Disease
  23. 23. Tay-Sachs Major ClinicalFeaturespsychomotor retardationpsychomotor deteriorationblindnessapathyunresponsivehypotoniaseizuresEEG abnormalitiesmegalencephalyabsence of hexosaminidase Aearly death (2-4 years)
  24. 24. Cystic Fibrosis
  25. 25. 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
  26. 26. 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
  27. 27. Niemann-Pick Disease
  28. 28. 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
  29. 29. MucopolysaccharidosesMPS
  30. 30. MPS General ClinicalFeatures mental retardation frontal bossing hypertelorism prominent eyes gingival hypertrophy gapped teeth thick tongue storage ofmucopolysaccharides inbody tissues corneal clouding hepatosplenomegaly hand anomalies still joints congestive heart failure pneumonia kyphosis
  31. 31. Hurler’s SyndromeMPS Type 1
  32. 32. Hurler Major ClinicalFeatures 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
  33. 33. Sanfilippo SyndromeMPS Type 111
  34. 34. Sanfilippo Major ClinicalFeaturesaccelerated growth to 3 yearsgrowth retardation after 3 yearsmental deteriorationmildly coarse faciesvariable hepatomegalyabnormal teethmild cardiac anomalies
  35. 35. Scheie’s SyndromeMPS Type V
  36. 36. Scheie’s Major ClinicalFeaturesnormal intelligencecorneal cloudingjoint limitation in handsaortic valvular defectbody hirsutismherniasbroad hands and feet
  37. 37. von Gierke’s Disease(Glycogen Storage Disorder Type I)
  38. 38. Von Gierke’s Major ClinicalFeaturesabsence of liver glucose–6-phosphatasehypoglycemiashort staturegood prognosisaccumulation of glycogen in liver andkidneys
  39. 39. Ehlers-Danlos Syndrome
  40. 40. Ehlers-Danlos Major ClinicalFeatureshypermobile “lop” earsvelvety skinfragile hyperextensive skinhyperextensible jointseasy to bruisemitral valve prolapsecollagen defect
  41. 41. Progeria
  42. 42. Progeria Major ClinicalFeatures alopecia thin skin hypoplasia of nails loss of subcutaneous fat skeletal hypoplasia,dysplasia, degeneration delayed eruption of teeth atherosclerosis mild elevation of serumcholesterol premature aging normal intelligence
  43. 43. Spinal Muscular AtrophyType I(Werdnig-Hoffman Disease)
  44. 44. SMA Type I ClinicalFeatures hypotonia weakness decreased or absent deep tendonreflexes pulmonary infection respiratory failure rapid coarse to death at early age
  45. 45. Homocystinuria
  46. 46. Homocystinuria ClinicalFeatures abnormalities ofskeletal system genu valgum scoliosis kyphosis pectus excavatum osteoporosis restricted joint mobility ectopia lentis (downward) thrombosis mental retardation
  47. 47. Single Gene DefectsSingle Gene DefectsAutosomal recessive Autosomal dominantX-linked recessiveX-linked dominant
  48. 48. Autosomal dominant (AD) One Trait, 2 allelesA = dominant abnormal allelea = recessive normal alleleHomozygous dominant = affected, often lethal (AA)Heterozygous dominant = affected (Aa)Homozygous recessive = normal (aa)HBD/SGD/AD
  49. 49. Autosomal Dominant (AD) One parent affected (usuallyheterozygous) Second parent normal 50% chance for affected offspring 50% chance for normal offspring Males and females equallyaffected Penetrance Variable expressionHBD/SGD/AD
  50. 50. AD Pedigree “Vertical” Equal numbers of males andfemales affected One parent genotypically &phenotypically normal Other parent heterozygousaffected 50% recurrence riskHBD/SGD/AD
  51. 51. AD Disorders Marfan’s Syndrome Huntington’s Chorea Osteogenesis imperfecta Neurofibromatosis Retinoblastoma Tuberous sclerosis Apert’s Syndrome Multiple polyposis ofcolonHBD/SGD/AD
  52. 52. Marfan Syndrome
  53. 53. Marfan Clinical Features abnormalities ofskeletal system kyphoscoliosis pectus excavatum ectopia lentis (upward) myopia dilation of ascending aorta mitral regurgitation dissecting aneurysm retinal detachment small lens
  54. 54. Crouzon’s Syndrome
  55. 55. Crouzon Major ClinicalFeaturesshallow orbitspremature craniosynostosismaxillary hypoplasiafrontal bossingconductive hearing lossmental retardation (occasional)seizures (occasional)
  56. 56. Apert’s Syndrome
  57. 57. Apert Major ClinicalFeaturesmental deficiencyoccasional normal intelligenceirregular craniosynostosis (“Tower” skull)midfacial hypoplasiasyndactyly (“mitten hand”)hypertelorismstrabismussmall nosemaxillary hypoplasia
  58. 58. Treacher-Collin’sSyndrome
  59. 59. Treacher-Collin ClinicalFeatures mandibular hypoplasia lower lid colomboma malformation of auricles malar hypoplasia (with orwithout cleft in zygomatic bone) external ear canal defect conductive deafness cleft palate incompetent soft palate
  60. 60. Cherubism
  61. 61. Cherubism Major ClinicalFeaturestumor-like facial changesbenign dysplasia of jaw boneserious dental anomalies
  62. 62. Neurofibromatosis
  63. 63. NeurofibromatosisMajor 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)
  64. 64. AchondroplasticDwarfism
  65. 65. Achondroplastic DwarfismMajor Clinical Features megalocephaly short limbs low nasal bridge caudal narrowing ofspinal cord lumbar lordosis skeletal anomalies mild hypotonia normal intelligence
  66. 66. Osteogenesis Imperfecta
  67. 67. Osteogenesis ImperfectaMajor Clinical Features “congenita” = severe form multiple intrauterinefractures “tarda” = later onset form susceptibility to bonefracture bone deformities joint laxity short stature growth retardation kyphoscoliosis pectus excavatum yellow teeth thin skin blue sclerae
  68. 68. Holt-Oram Syndrome
  69. 69. Holt-OramMajor Clinical Featuresdefect of upper limb and shoulder girdlethumb hypoplasia or phocomeliaasymmetryauricular septal defectcardiac arrythmiahypoplasia of distal blood vessels
  70. 70. Single Gene DefectsSingle Gene DefectsAutosomal recessiveAutosomal dominant X-linked recessiveX-linked dominant
  71. 71. X-linked recessive (XR)One trait, 2 allelesA = dominant normal allelea = recessive abnormal alleleMust consider which parent has theabnormal gene when assessing riskHBD/SGD/XR
  72. 72. 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
  73. 73. 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 female50% homozygous normal female Males and females NOT equallyaffectedHBD/SGD/XR
  74. 74. XR Pedigree “Criss-cross” inheritance pattern Female carriers risk affected sons Female carriers risk carrierdaughters Often lethal to males Transmission through normalfemales producing affected males No male to male transmissionHBD/SGD/XR
  75. 75. XR Pedigree “Criss-cross” inheritance pattern Female carriers risk affected sons Female carriers risk carrierdaughters Often lethal to males Transmission through normalfemales producing affected males No male to male transmissionHBD/SGD/XR
  76. 76. XR DisordersDuchenne’s Muscular DystrophyHemophiliaHunter’s SyndromeAarskog’s SyndromeLesch-Nyhan SyndromePyruvate dehydrogenase deficiencyHBD/SGD/XR
  77. 77. Muscular Dystrophy
  78. 78. Muscular DystrophyMajor 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
  79. 79. Aarskog Syndrome
  80. 80. Aarskog Major ClinicalFeatures round face small nose brachydactyly slight to moderateshort stature mild pectus excavatum prominent umbilicus shawl scrotum dull normal intelligence hypodontia
  81. 81. Lesch-Nyhan Syndrome
  82. 82. Lesch-NyhanMajor Clinical Features spasticity choreoathetosis self-mutilation autistic behavior growth deficiency gout HGPRT deficiency (enzyme of purinemetabolism)
  83. 83. Hunter Syndrome(MPS Type II)
  84. 84. Hunter Major ClinicalFeatures coarse facies growth retardation stiff joints no corneal clouding neurological deterioration severe mental retardation macrocephaly hepatosplenomegaly hernias progressive deafness abnormal dentition
  85. 85. Bruton’sAgammaglobulinemia
  86. 86. Bruton Major ClinicalFeatures normal appearance absence of serum antibodies risk of bacterial infection risk of pneumonia strong predisposition to rheumatoidarthritis and to cancer
  87. 87. Single Gene DefectsSingle Gene DefectsAutosomal recessiveAutosomal dominantX-linked recessive X-linked dominant
  88. 88. X-linked dominant (XD) One trait, 2 allelesA = dominant abnormal allelea = recessive normal allele Must consider which parent has theabnormal gene when assessing riskHBD/SGD/XD
  89. 89. 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
  90. 90. 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 equallyaffectedHBD/SGD/XDAffectedFatherNormalMotherAffected Normal Affected Normalfemale male female male
  91. 91. XD Pedigree Homozygous females often moreseverely affected than hemizygousmales Affected females risk affectedsons and affected daughters Affected males risk affecteddaughters No male to male transmission Difficult to distinguish fromautosomal dominantHBD/SGD/XD
  92. 92. XD Disorders Vitamin D resistant rickets Browning of the enamel of the teeth Albright’s hereditary osteodystrophy Taybi SyndromeHBD/SGD/XD
  93. 93. Vitamin D-resistantRickets withhypophosphatemia
  94. 94. Resistant RicketsMajor Clinical Features bone deficiencies (“bowed” legs) dental anomalies decreased phosphate in serum short stature normal intelligence
  95. 95. Heritable Birth DefectsHeritable Birth DefectsSingle Gene Defects Chromosomal AbnormalitiesMultifactorial DisordersNon-classical DisordersCancer Genetics
  96. 96. Populations at Risk forChromosome 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
  97. 97. 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
  98. 98. 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)
  99. 99. Chromosomes: A Review Homologous pairs Autosomes/sex chromosomes Karyotype: arrange by size Centromere position:metacentricsubmetacentric/p/qacrocentric/satellites/rDNA G Banding NomenclatureHBD/CA
  100. 100. Normal Female: 46,XX
  101. 101. Normal Male: 46,XY
  102. 102.  Acrocentric chromosomehaving a “bad hair day” Note chromatids “Fibrous” appearance No bands apparentChromosomes: A ReviewHBD/CA
  103. 103. Chromosomes: A Review Idiogram: standard for bands p and q arms centromere position bands numbered satellited chromosomesHBD/CA
  104. 104. Chromosomes: A Review chromosome #1 idiogram largest, metacentric p and q arms with bandsand sub-bands different band densityshown G-banded metaphasechromosome at lower leftHBD/CApq3211234
  105. 105. 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 oftwo, non-homologous chromosomesHBD/CA
  106. 106. Chromosomal Abnormalitiesamong Spontaneous AbortionsType % (n=287)45,XO 23.7Other sex aneuploids 1.0Autosomal trisomies 49.8Triploids 13.2Tetraploids 4.2Rearrangementsbalanced 0.3unbalanced 3.1Other 4.5
  107. 107. Chromosomal AnomaliesRobertsonian translocationbreak break21 2114 14HBD/CA
  108. 108. Chromosomal AnomaliesPossible Gametes for Trans carrier14, 2114/2114 21 14/21 21, 14/2114, 14/21Translocation carrier 1421HBD/CA
  109. 109. Chromosomal AnomaliesCarrier x Normal Offspring14, 21 14, 21 normal14/21 14,21 normal carrier21, 14/21 14,21 translocation Down’s14, 14/21 14,21 “trisomy” 14 (lethal)14 14,21 monosomy 21 (lethal)21 14,21 monosomy 14 (lethal)HBD/CA
  110. 110. Chromosomal Anomalies Theoretical risk (omitting lethal conditions):1/3 normal1/3 translocation carrier (normal)1/3 Down Syndrome Actual risk for Down Syndrome:1/10 if female is translocation carrier1/20 if male is translocation carrierHBD/CA
  111. 111. Chromosomal Anomalies Abnormal number/kind of chromosomes Autosomal anomalies Sex chromosome anomaliesHBD/CA
  112. 112. Autosomal AnomaliesGeneral features:Mental retardation (MR)Growth retardation (GR)Multiple congenital anomaliesPoor to moderate viabilityPrenatally diagnosableAssociated with spontaneous abortion (Sab)HBD/CA/Auto
  113. 113. Autosomal Anomalies Trisomy 13 - Patau Syndrome Trisomy 18 - Edward Syndrome Trisomy 21 - Down Syndrome 5p-deletion - Cri-du-chat SyndromeHBD/CA/Auto
  114. 114. Autosomal Abnormalities
  115. 115. Trisomy 21Down Syndrome
  116. 116. Down Syndrome 47,XY,+21
  117. 117. Nomenclature47, XX, 21+Female with Down Syndrome47, XY, 21+Male with Down Syndrome
  118. 118. Trisomy 21Major Clinical Features mental retardation slanted palpebralfissures epicanthal folds small, round, flat face small mouth,protruding tongue congenital heartproblems Brushfield spots (iris) small, hypoplasticears simian creases hypotonia, lax joints,hyperextensive
  119. 119. 45, XY, D- G-, t(DqGq)
  120. 120. 46, XY, D-, t(DqGq)
  121. 121. Trisomy 13Patau Syndrome
  122. 122. Patau Syndrome 47,XY,13+
  123. 123. Trisomy 13Major 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
  124. 124. Trisomy 18Edward’ Syndrome
  125. 125. Edward’ Syndrome 47,XX,+18
  126. 126. Trisomy 18Major Clinical Features mental retardation growth retardation short neck cleft lip/palate dislocatedhips/abnormal pelvis deformed, low-set ears hypertonia congenital heartdisease horseshoe kidneys hydronephrosis short sternum pyloric stenosis
  127. 127. Cri du chat Syndrome(5p-)
  128. 128. Cri du Chat 5p-
  129. 129. Cri du chatMajor Clinical Features distinctive cat-like cry profound developmentalretardation severe mental retardation microcephaly hypotonia hypertelorism congenital heart disease round, moon-shaped face large mouth, short philtrum low set ears hand and foot abnormalities
  130. 130. Sex ChromosomeAbnormalities
  131. 131. Sex Chromosome Anomalies General features:Some growth retardation (GR)Reproductive anomalies/problemsGood viabilityPrenatally diagnosableAssociated with spontaneous abortion (Sab)HBD/CA/Sex
  132. 132. 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 SyndromeHBD/CA/Sex
  133. 133. Turner’s Syndrome
  134. 134. Turner’s Syndrome 45,X
  135. 135. Turner’s SyndromeMajor Clinical Features female phenotype short (less than 5 feet) primary amenorrhea low estrogen levels maldevelopment of theovaries sterility webbing of the skin ofthe neck wide-spaced nipples edema at birth cardiovascularproblems
  136. 136. Klinefelter’s Syndrome
  137. 137. Klinefelter’s Syndrome47,XXY
  138. 138. Klinefelter’s SyndromeMajor 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
  139. 139. Chromosome InstabilitySyndromes
  140. 140. Bloom’s Syndrome
  141. 141. Bloom’s SyndromeMajor Clinical Features prenatal onset ofgrowth deficiency short stature malar hypoplasia telangiectatic erythemaof the face mild microcephaly mild mental deficiency(occasional) sensitivity to light increased rate ofchromosome breakage predisposition tomalignancy
  142. 142. Fanconi’s Anemia
  143. 143. Fanconi’s AnemiaMajor Clinical Features short stature radial hypoplasia hyperpigmentation pancytopenia absent thumbs progressive muscularwasting hypoplastic and/ormalformed kidneys congenital dislocationof the hip
  144. 144. Heritable Birth DefectsHeritable Birth DefectsSingle Gene DefectsChromosomal Abnormalities Multifactorial DisordersNon-classical DisordersCancer Genetics
  145. 145. Risk to Relatives for SameMalformation as Index CaseMalformation Risk (population risk compared to degree ofrelationship)Pop First Second ThirdCleft 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
  146. 146. Multifactorial Inheritance One trait Multifactorial: many “factors” governing 1 trait genes plus environment Polygenic: many loci more than 2 alleles/locusHBD/MF
  147. 147. Multifactorial InheritanceenvironmentPotential ActualGenotype Phenotype(genes) (appearance)HBD/MF
  148. 148. 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 malformationsHBD/MF
  149. 149. Cleft lip/Palate
  150. 150. Cleft lip/PalateMajor 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
  151. 151. Midline Dysplasia
  152. 152. Midline DysplasiaMajor 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
  153. 153. Neural Tube Defects (NTD)
  154. 154. Neural Tube Defects anencephaly myelomeningocoele meningocoele encephalocoele
  155. 155. AnencephalyMajor Clinical Features partial or complete absence of calvarium andcranial vault missing cerebral hemispheres incompatible with postnatal life
  156. 156. EncephalocoeleMajor Clinical Features herniation of brain and meninges through adefect in the skull
  157. 157. Spina BifidaMajor Clinical Features defect in spinal cord with sac-like protrusion open or closed wide variability dependent upon locationalong spine prognosis based on tissue in sac: Myelomeningocoele: includes meninges, spinal cord,and nerves Meningocoele: includes meninges and is covered
  158. 158. Infant of Diabetic Mother
  159. 159. Infant of Diabetic MotherMajor 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
  160. 160. Hypospadias Glandis
  161. 161. Hypospadias GlandisMajor Clinical Features opening of the male urethra on theundersurface of the penis cutaneous or fibrous chordee complications may include: microphallus cryptorchidism inguinal hernia bifid scrotum
  162. 162. Exstrophy of Bladder(ectopia vesicae)
  163. 163. Exstrophy of BladderMajor 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
  164. 164. Gastroschisis
  165. 165. GastroschisisMajor 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
  166. 166. Omphalocoele
  167. 167. OmphalocoeleMajor Clinical Features increased MSAFP levels herniation of abdominal region includingumbilicus sac covering the anomaly increased risk of infection low birth weight small abdominal cavity
  168. 168. Sirenomelia
  169. 169. SirenomeliaMajor Clinical Features alteration in earlyvascular development absent or incompletedevelopment of caudalstructures single lower extremitywith posterioralignment of kneesand feet vertebral defects imperforate anus absence of rectum absence of internal &external genitalia renal agenesis absence of bladder absence of sacrum
  170. 170. Cystic Hygroma
  171. 171. Cystic HygromaMajor 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
  172. 172. Rubenstein-Taybi Syndrome
  173. 173. Rubenstein-Taybi SyndromeMajor Clinical Features short stature mental retardation EEG abnormality epicanthal folds hypoplastic maxillawith narrow palate low-set/malformed ears hand and foot anomalies cryptorchidism cardiac murmurs renal anomalies small head
  174. 174. Cornelia de Lange Syndrome
  175. 175. Cornelia de Lange SyndromeMajor Clinical Features short stature mental retardation hypertonicity low-pitched, weak,growling cry microbrachycephaly bushy eyebrows small nose high arched palate micrognathia hirsutism hypoplastic nipples andumbilicus hand and foot anomalies
  176. 176. Amniotic Band Syndrome
  177. 177. Amniotic Band SyndromeMajor 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
  178. 178. Heritable Birth DefectsHeritable Birth DefectsSingle Gene DefectsChromosomal AbnormalitiesMultifactorial Disorders Non-classical DisordersCancer Genetics
  179. 179. Non-Classical InheritanceUniparental Disomy (UPD)Trinucleotide Repeat Disorders(TNR)Mitochondrial/Maternal Inheritance
  180. 180. Uniparental Disomy(UPD)
  181. 181. Uniparental disomy (UPD) Uniparental disomy: both homologuescome from the same parent, none fromthe othereg: 2 #7 chromosomes from mom, none from dad Isodisomy vs heterodisomyHBD/NCI/UPD
  182. 182. Uniparental disomy (UPD)female male7A 7B 7C 7DIsodisomy 7A 7AHeterodisomy 7A 7BHBD/NCI/UPD
  183. 183. 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 chromosomesHBD/NCI/UPD
  184. 184. Uniparental disomy (UPD) Why does it make a difference if anindividual has two maternal homologues ortwo paternal homologues or onehomologue fromm each?HBD/NCI/UPD
  185. 185. Uniparental disomy (UPD) Genetic Imprinting: “…modifications of genetic material that takeplace depending upon whether the informationis derived from the mother or the father…”Judith Hall (1990) chromosomes are “imprinted” by the parentHBD/NCI/UPD
  186. 186. Uniparental disomy (UPD) Early mouse experiments Enucleate an egg cellleaving only cytoplasm Add 2 maternal genomes(diploid female cell)OR Add 2 paternal genomes(diploid male cell)HBD/NCI/UPDControl 2 maternalgenomes2 paternalgenomesYSEEEM
  187. 187. Prader-Willi Syndrome(Chromosomal)
  188. 188. Prader-WilliMajor Clinical Features mental retardation obesity dental caries macrophagy skin lesions small hands/feet cryptorchidism small genitalia 15q11-q13 deletion(70% paternal)
  189. 189. Angelman Syndrome(Chromosomal)
  190. 190. AngelmanMajor Clinical Features severe to profound mental retardation inappropriate, excessive laughter epilepsy aphasia 15q11-q13 deletion (80% maternal)
  191. 191. Trinucleotide Repeat(TNR) Disorders
  192. 192. Trinucleotide Repeat Disorders TNR: repeat of 3 (tri) nucleotides from 30 to100s of copies(eg: CGGCGGCGGCGGCGGCGG) premutation: 50 - 230 repeats full mutation: > 230 repeatsHBD/NCI/TNR
  193. 193. Trinucleotide Repeat Disorders Dynamic mutations: “…the capability of a trinucleotide to expandinto multiple copies within one generation…the ability to increase in copy number overseveral generations…”heritable, unstable DNAHBD/NCI/TNR
  194. 194. Trinucleotide Repeat Disorders Anticipation: the observation that a disease becomesprogressively worse and demonstrates earlieronset in subsequent generations; maybe due to or related to dynamic mutationsand TNRHBD/NCI/TNR
  195. 195. Trinucleotide Repeat Disorders Huntington’s Disease Fragile X Syndrome Myotonic dystrophy Kennedy Disease Spinocerebellar ataxia Machado-Joseph diseaseHBD/NCI/TNR
  196. 196. Myotonic Dystrophy(AD)
  197. 197. Myotonic DystrophyMajor 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
  198. 198. Huntington’s Chorea(AD)
  199. 199. Huntington’s ChoreaMajor Clinical Features chorea dementia clumsy gait indistinct speech emotional instability paranoia progressive deterioration late onset of symptoms
  200. 200. Fragile X Syndrome(Martin-Bell Syndrome)(Chromosomal)
  201. 201. Fragile XMajor Clinical Features Males: large loppy ears prominent foreheadand jaw large testes educable to severe MR 20% unaffected,transmitting males Females: slow learners mild MR shy some affected carriers
  202. 202. Fragile X Syndrome
  203. 203. Fragile X
  204. 204. Mitochondrial/MaternalInheritance
  205. 205. Mitochondrial Inheritance Mitochondria: semi-autonomous, circular, naked DNA (~prokaryoticchromosome) 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 DNAHBD/NCI/Mito
  206. 206. Mitochondrial InheritanceHeteroplasmy = different % of normal &abnormal mitochondria in single cells or tissuesand or andHBD/NCI/Mitox x x x x xo o o o o oo o o o o oO o ox x x xo o o o ox x o o oo o o oxo o o o oo o o ox x x x xo o o
  207. 207. Mitochondrial Inheritance Disease phenotype dependent upon: gene(s) involved type of mutation(missense/nonsense/deletion) % normal vs abnormal mitochondria tissue involvedHBD/NCI/Mito
  208. 208. 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
  209. 209. Myoclonic Encephalopathy withRagged Red Fibers(MERRF)
  210. 210. MERRF Major ClinicalFeaturesataxiaepilepsyhypotoniamuscle weaknesslactic acidemiaragged red fibers seen in muscle biopsyabnormal energy metabolism in muscles
  211. 211. Heritable Birth DefectsHeritable Birth DefectsSingle Gene DefectsChromosomal AbnormalitiesMultifactorial DisordersNon-classical Disorders Cancer Genetics
  212. 212. Basic Definitions of TermsProto-oncogene = a normal gene which controls celldivision (“speeds up”)Oncogene = a mutated or abnormal proto-oncogene whichinduces cell division at the wrong time, place or rateTumor Suppressor (TS) gene = a normal gene whichcontrols cell division (“slows down”)Mutated TS gene = an abnormal gene which fails to stopcell division at the appropriate time or place
  213. 213. General Classes of Cancer Breast Colorectal Leukemia Lymphoma Skin Ovarian Pancreatic Prostate Testicular UterineHBD/CG
  214. 214. Specific Cancers CML, AML (leukemias) Burkitt’s, Hodgkin’s, non-Hodgkin’s(lymphomas) Retinoblastoma (retina) LiFraumeni Syndrome
  215. 215. Retinoblastoma(AD)
  216. 216. RetinoblastomaMajor 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
  217. 217. Chronic MyelogenousLeukemia (CML)
  218. 218. 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
  219. 219. 46,XX,Ph1+
  220. 220. Non-Heritable BirthNon-Heritable BirthDefectsDefectsEnvironmental Teratogens
  221. 221. “Non-Heritable” Birth Defects(NHBD) teratogen = any chemical, biological orphysical agent that increases the probabilityof a birth defect
  222. 222. “Non-Heritable” Birth Defects drugs(OTC/illegal) chemicals X-rays oxygen deprivation toxins infections accidents/injuries alcohol nicotine caffeine poisons
  223. 223. Fetal Alcohol Syndrome
  224. 224. Fetal Alcohol SyndromeMajor 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 theheart, kidney, eye,brain, ear, skeleton
  225. 225. Fetal Rubella Effects
  226. 226. Fetal Rubella EffectsMajor Clinical Features deafness cataracts patent ductus arteriosus mental retardation glaucoma septal defects thrombocytopenia hepatosplenomegaly interstitial pneumonia
  227. 227. Fetal Hydantoin Syndrome
  228. 228. Fetal HydantoinMajor Clinical Featuresmental retardationdistal phalangeal hypoplasiafacial cleftscardiac anomalies
  229. 229. Fetal Warfarin Effects
  230. 230. Fetal Warfarin EffectsMajor Clinical Featuresnasal hypoplasiadepressed nasal bridgeskeletal stipplingmild hypoplasia of nailsshort fingerslow birth weightmental retardation
  231. 231. Hyperthermia
  232. 232. HyperthermiaMajor Clinical Features defects dependent upontime of exposure mental deficiency hypertonicity neurogenic contractures seizures hormone deficiency microphthalmia micrognathia midfacial hypoplasia external ear anomalies cleft lip/palate microcephaly
  233. 233. Pierre-Robin Syndrome
  234. 234. Pierre-Robin SyndromeMajor Clinical Features micrognathia glossoptosis cleft soft palate early mandibular hypoplasia upper respiratory obstruction failure to thrive
  235. 235. Potter’s Syndrome
  236. 236. Potter’s SyndromeMajor Clinical Features renal agenesis oligohydramnios multiple malformations growth deficiency fetal compression in utero altered facies limb positioning defects
  237. 237. Amelia/Phocomelia
  238. 238. Amelia/PhocomeliaMajor 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
  239. 239. Radiation Exposure
  240. 240. Radiation ExposureMajor 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 ifbetween 2 and 4 weeks gestation 2 rads: very low increased risk
  241. 241. Caffeine/Tobacco(“stimulants”)
  242. 242. Caffeine/TobaccoMajor 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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