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Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
Comprehensive survey of human genetic diseases
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Comprehensive survey of human genetic diseases

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  • 1. Medical GeneticsMedical GeneticsFor Medical StudentFor Medical Student
  • 2. Overview
  • 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. 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. 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. Terms & Definitions birth defect genetic disorder malformation deformation disruption sequence syndrome association morphology dysmorphology variability heterogeneity pleiotrophy organogenesis morphogenesis hyperplasia hypoplasia dysplasia
  • 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. Modes of Inheritance &Selected Examples
  • 9. Heritable Birth Defects (HBD) Single Gene Defects (SGD) Chromosomal Anomalies (CA) Multifactorial Inheritance (MF) Non-Classical Inheritance (NCI) Cancer Genetics (CG)
  • 10. “Non-Heritable” Birth Defects (NHBD) Environmental teratogensteratogen = any chemical, biologicalor physical agent that increases theprobability of a birth defect
  • 11. Heritable Birth DefectsHeritable Birth Defects(HBD)(HBD) Single Gene DefectsChromosomal AbnormalitiesMultifactorial DisordersNon-classical DisordersCancer Genetics
  • 12. Single Gene DefectsSingle Gene Defects Autosomal recessiveAutosomal dominantX-linked recessiveX-linked dominantHBD
  • 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. 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. AR Pedigree Pedigree symbols Proband “Horizontal” Equal numbers ofmales and females Phenotypically normalparents 25% recurrence riskHBD/SGD/AR
  • 16. AR Disorders PKU - phenylketonuria Galactosemia Homocystinuria Cystic fibrosis Tay-Sachs Sickle cell anemiaHBD/SGD/AR
  • 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. 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. 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. PhenylketonuriaPKU
  • 21. PKU Major ClinicalFeatures MR Agitated behavior EEG abnormalities hyperactive reflexes muscular hypertonicity inability to talk inability to walk tremors seizures
  • 22. Tay-Sachs Disease
  • 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. Cystic Fibrosis
  • 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. 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. Niemann-Pick Disease
  • 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. MucopolysaccharidosesMPS
  • 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. Hurler’s SyndromeMPS Type 1
  • 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. Sanfilippo SyndromeMPS Type 111
  • 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. Scheie’s SyndromeMPS Type V
  • 36. Scheie’s Major ClinicalFeaturesnormal intelligencecorneal cloudingjoint limitation in handsaortic valvular defectbody hirsutismherniasbroad hands and feet
  • 37. von Gierke’s Disease(Glycogen Storage Disorder Type I)
  • 38. Von Gierke’s Major ClinicalFeaturesabsence of liver glucose–6-phosphatasehypoglycemiashort staturegood prognosisaccumulation of glycogen in liver andkidneys
  • 39. Ehlers-Danlos Syndrome
  • 40. Ehlers-Danlos Major ClinicalFeatureshypermobile “lop” earsvelvety skinfragile hyperextensive skinhyperextensible jointseasy to bruisemitral valve prolapsecollagen defect
  • 41. Progeria
  • 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. Spinal Muscular AtrophyType I(Werdnig-Hoffman Disease)
  • 44. SMA Type I ClinicalFeatures hypotonia weakness decreased or absent deep tendonreflexes pulmonary infection respiratory failure rapid coarse to death at early age
  • 45. Homocystinuria
  • 46. Homocystinuria ClinicalFeatures abnormalities ofskeletal system genu valgum scoliosis kyphosis pectus excavatum osteoporosis restricted joint mobility ectopia lentis (downward) thrombosis mental retardation
  • 47. Single Gene DefectsSingle Gene DefectsAutosomal recessive Autosomal dominantX-linked recessiveX-linked dominant
  • 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. 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. AD Pedigree “Vertical” Equal numbers of males andfemales affected One parent genotypically &phenotypically normal Other parent heterozygousaffected 50% recurrence riskHBD/SGD/AD
  • 51. AD Disorders Marfan’s Syndrome Huntington’s Chorea Osteogenesis imperfecta Neurofibromatosis Retinoblastoma Tuberous sclerosis Apert’s Syndrome Multiple polyposis ofcolonHBD/SGD/AD
  • 52. Marfan Syndrome
  • 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. Crouzon’s Syndrome
  • 55. Crouzon Major ClinicalFeaturesshallow orbitspremature craniosynostosismaxillary hypoplasiafrontal bossingconductive hearing lossmental retardation (occasional)seizures (occasional)
  • 56. Apert’s Syndrome
  • 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. Treacher-Collin’sSyndrome
  • 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. Cherubism
  • 61. Cherubism Major ClinicalFeaturestumor-like facial changesbenign dysplasia of jaw boneserious dental anomalies
  • 62. Neurofibromatosis
  • 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. AchondroplasticDwarfism
  • 65. Achondroplastic DwarfismMajor Clinical Features megalocephaly short limbs low nasal bridge caudal narrowing ofspinal cord lumbar lordosis skeletal anomalies mild hypotonia normal intelligence
  • 66. Osteogenesis Imperfecta
  • 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. Holt-Oram Syndrome
  • 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. Single Gene DefectsSingle Gene DefectsAutosomal recessiveAutosomal dominant X-linked recessiveX-linked dominant
  • 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. 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. 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. 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. 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. XR DisordersDuchenne’s Muscular DystrophyHemophiliaHunter’s SyndromeAarskog’s SyndromeLesch-Nyhan SyndromePyruvate dehydrogenase deficiencyHBD/SGD/XR
  • 77. Muscular Dystrophy
  • 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. Aarskog Syndrome
  • 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. Lesch-Nyhan Syndrome
  • 82. Lesch-NyhanMajor Clinical Features spasticity choreoathetosis self-mutilation autistic behavior growth deficiency gout HGPRT deficiency (enzyme of purinemetabolism)
  • 83. Hunter Syndrome(MPS Type II)
  • 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. Bruton’sAgammaglobulinemia
  • 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. Single Gene DefectsSingle Gene DefectsAutosomal recessiveAutosomal dominantX-linked recessive X-linked dominant
  • 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. 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. 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. 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. XD Disorders Vitamin D resistant rickets Browning of the enamel of the teeth Albright’s hereditary osteodystrophy Taybi SyndromeHBD/SGD/XD
  • 93. Vitamin D-resistantRickets withhypophosphatemia
  • 94. Resistant RicketsMajor Clinical Features bone deficiencies (“bowed” legs) dental anomalies decreased phosphate in serum short stature normal intelligence
  • 95. Heritable Birth DefectsHeritable Birth DefectsSingle Gene Defects Chromosomal AbnormalitiesMultifactorial DisordersNon-classical DisordersCancer Genetics
  • 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. 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. 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. Chromosomes: A Review Homologous pairs Autosomes/sex chromosomes Karyotype: arrange by size Centromere position:metacentricsubmetacentric/p/qacrocentric/satellites/rDNA G Banding NomenclatureHBD/CA
  • 100. Normal Female: 46,XX
  • 101. Normal Male: 46,XY
  • 102.  Acrocentric chromosomehaving a “bad hair day” Note chromatids “Fibrous” appearance No bands apparentChromosomes: A ReviewHBD/CA
  • 103. Chromosomes: A Review Idiogram: standard for bands p and q arms centromere position bands numbered satellited chromosomesHBD/CA
  • 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. 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. 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. Chromosomal AnomaliesRobertsonian translocationbreak break21 2114 14HBD/CA
  • 108. Chromosomal AnomaliesPossible Gametes for Trans carrier14, 2114/2114 21 14/21 21, 14/2114, 14/21Translocation carrier 1421HBD/CA
  • 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. 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. Chromosomal Anomalies Abnormal number/kind of chromosomes Autosomal anomalies Sex chromosome anomaliesHBD/CA
  • 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. Autosomal Anomalies Trisomy 13 - Patau Syndrome Trisomy 18 - Edward Syndrome Trisomy 21 - Down Syndrome 5p-deletion - Cri-du-chat SyndromeHBD/CA/Auto
  • 114. Autosomal Abnormalities
  • 115. Trisomy 21Down Syndrome
  • 116. Down Syndrome 47,XY,+21
  • 117. Nomenclature47, XX, 21+Female with Down Syndrome47, XY, 21+Male with Down Syndrome
  • 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. 45, XY, D- G-, t(DqGq)
  • 120. 46, XY, D-, t(DqGq)
  • 121. Trisomy 13Patau Syndrome
  • 122. Patau Syndrome 47,XY,13+
  • 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. Trisomy 18Edward’ Syndrome
  • 125. Edward’ Syndrome 47,XX,+18
  • 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. Cri du chat Syndrome(5p-)
  • 128. Cri du Chat 5p-
  • 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. Sex ChromosomeAbnormalities
  • 131. Sex Chromosome Anomalies General features:Some growth retardation (GR)Reproductive anomalies/problemsGood viabilityPrenatally diagnosableAssociated with spontaneous abortion (Sab)HBD/CA/Sex
  • 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. Turner’s Syndrome
  • 134. Turner’s Syndrome 45,X
  • 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. Klinefelter’s Syndrome
  • 137. Klinefelter’s Syndrome47,XXY
  • 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. Chromosome InstabilitySyndromes
  • 140. Bloom’s Syndrome
  • 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. Fanconi’s Anemia
  • 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. Heritable Birth DefectsHeritable Birth DefectsSingle Gene DefectsChromosomal Abnormalities Multifactorial DisordersNon-classical DisordersCancer Genetics
  • 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. Multifactorial Inheritance One trait Multifactorial: many “factors” governing 1 trait genes plus environment Polygenic: many loci more than 2 alleles/locusHBD/MF
  • 147. Multifactorial InheritanceenvironmentPotential ActualGenotype Phenotype(genes) (appearance)HBD/MF
  • 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. Cleft lip/Palate
  • 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. Midline Dysplasia
  • 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. Neural Tube Defects (NTD)
  • 154. Neural Tube Defects anencephaly myelomeningocoele meningocoele encephalocoele
  • 155. AnencephalyMajor Clinical Features partial or complete absence of calvarium andcranial vault missing cerebral hemispheres incompatible with postnatal life
  • 156. EncephalocoeleMajor Clinical Features herniation of brain and meninges through adefect in the skull
  • 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. Infant of Diabetic Mother
  • 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. Hypospadias Glandis
  • 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. Exstrophy of Bladder(ectopia vesicae)
  • 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. Gastroschisis
  • 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. Omphalocoele
  • 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. Sirenomelia
  • 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. Cystic Hygroma
  • 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. Rubenstein-Taybi Syndrome
  • 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. Cornelia de Lange Syndrome
  • 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. Amniotic Band Syndrome
  • 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. Heritable Birth DefectsHeritable Birth DefectsSingle Gene DefectsChromosomal AbnormalitiesMultifactorial Disorders Non-classical DisordersCancer Genetics
  • 179. Non-Classical InheritanceUniparental Disomy (UPD)Trinucleotide Repeat Disorders(TNR)Mitochondrial/Maternal Inheritance
  • 180. Uniparental Disomy(UPD)
  • 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. Uniparental disomy (UPD)female male7A 7B 7C 7DIsodisomy 7A 7AHeterodisomy 7A 7BHBD/NCI/UPD
  • 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. 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. 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. 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. Prader-Willi Syndrome(Chromosomal)
  • 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. Angelman Syndrome(Chromosomal)
  • 190. AngelmanMajor Clinical Features severe to profound mental retardation inappropriate, excessive laughter epilepsy aphasia 15q11-q13 deletion (80% maternal)
  • 191. Trinucleotide Repeat(TNR) Disorders
  • 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. 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. 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. Trinucleotide Repeat Disorders Huntington’s Disease Fragile X Syndrome Myotonic dystrophy Kennedy Disease Spinocerebellar ataxia Machado-Joseph diseaseHBD/NCI/TNR
  • 196. Myotonic Dystrophy(AD)
  • 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. Huntington’s Chorea(AD)
  • 199. Huntington’s ChoreaMajor Clinical Features chorea dementia clumsy gait indistinct speech emotional instability paranoia progressive deterioration late onset of symptoms
  • 200. Fragile X Syndrome(Martin-Bell Syndrome)(Chromosomal)
  • 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. Fragile X Syndrome
  • 203. Fragile X
  • 204. Mitochondrial/MaternalInheritance
  • 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. 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. Mitochondrial Inheritance Disease phenotype dependent upon: gene(s) involved type of mutation(missense/nonsense/deletion) % normal vs abnormal mitochondria tissue involvedHBD/NCI/Mito
  • 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. Myoclonic Encephalopathy withRagged Red Fibers(MERRF)
  • 210. MERRF Major ClinicalFeaturesataxiaepilepsyhypotoniamuscle weaknesslactic acidemiaragged red fibers seen in muscle biopsyabnormal energy metabolism in muscles
  • 211. Heritable Birth DefectsHeritable Birth DefectsSingle Gene DefectsChromosomal AbnormalitiesMultifactorial DisordersNon-classical Disorders Cancer Genetics
  • 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. General Classes of Cancer Breast Colorectal Leukemia Lymphoma Skin Ovarian Pancreatic Prostate Testicular UterineHBD/CG
  • 214. Specific Cancers CML, AML (leukemias) Burkitt’s, Hodgkin’s, non-Hodgkin’s(lymphomas) Retinoblastoma (retina) LiFraumeni Syndrome
  • 215. Retinoblastoma(AD)
  • 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. Chronic MyelogenousLeukemia (CML)
  • 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. 46,XX,Ph1+
  • 220. Non-Heritable BirthNon-Heritable BirthDefectsDefectsEnvironmental Teratogens
  • 221. “Non-Heritable” Birth Defects(NHBD) teratogen = any chemical, biological orphysical agent that increases the probabilityof a birth defect
  • 222. “Non-Heritable” Birth Defects drugs(OTC/illegal) chemicals X-rays oxygen deprivation toxins infections accidents/injuries alcohol nicotine caffeine poisons
  • 223. Fetal Alcohol Syndrome
  • 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. Fetal Rubella Effects
  • 226. Fetal Rubella EffectsMajor Clinical Features deafness cataracts patent ductus arteriosus mental retardation glaucoma septal defects thrombocytopenia hepatosplenomegaly interstitial pneumonia
  • 227. Fetal Hydantoin Syndrome
  • 228. Fetal HydantoinMajor Clinical Featuresmental retardationdistal phalangeal hypoplasiafacial cleftscardiac anomalies
  • 229. Fetal Warfarin Effects
  • 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. Hyperthermia
  • 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. Pierre-Robin Syndrome
  • 234. Pierre-Robin SyndromeMajor Clinical Features micrognathia glossoptosis cleft soft palate early mandibular hypoplasia upper respiratory obstruction failure to thrive
  • 235. Potter’s Syndrome
  • 236. Potter’s SyndromeMajor Clinical Features renal agenesis oligohydramnios multiple malformations growth deficiency fetal compression in utero altered facies limb positioning defects
  • 237. Amelia/Phocomelia
  • 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. Radiation Exposure
  • 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. Caffeine/Tobacco(“stimulants”)
  • 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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