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Genetics in Medicine

Genetics in Medicine. Nathaniel H. Robin, MD Department of Genetics University Alabama at Birmingham. Overview. Genetic evaluation Structural anomalies M alformation, deformation, dysplasia, disruption Multiple anomaly groupings Syndrome, association, sequence

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Genetics in Medicine

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  1. Genetics in Medicine Nathaniel H. Robin, MD Department of Genetics University Alabama at Birmingham

  2. Overview • Genetic evaluation • Structural anomalies • Malformation, deformation, dysplasia, disruption • Multiple anomaly groupings • Syndrome, association, sequence • Examples of genetic disorders • Chromosomal disorders • Single gene disorders • Genetic testing: past, present, and future

  3. Dysmorphology vs. Genomic Medicine

  4. Genomic Medicine “ … the routine use of genotypic analysis, usually in the form of DNA testing, to enhance the quality of medical care.” - A. Beaudet, 1998 ASHG Presidential Address (AJHG 64:1-13 1999) • Examples • - Inherited cancer (eg, BRCA1 and 2) • Asthma • Pharmacogenetics • - Warfarin, etc.

  5. Family history MI “female” cancer MI 68yr 45 yr 88 yr 87 yrs 28yr 35 yr 28 yr 29 yr 40 yr 2 wks SIDS Breast cancer 5 yr 3 yr 10 mo

  6. ‘Traditional’ genetics Dysmorphology (the study of abnormal form) • Evaluation of child (adult, fetus) with unusual facial characteristics +/- other abnormal findings in an effort to reach a genetic (syndrome) diagnosis

  7. Indications for a Genetics Consultation • Multiple major anomalies (Remember:mental retardation and growth failure are major anomalies) • One major anomaly with multiple minor anomalies • Multiple minor anomalies (The “FLK”-funny looking kid) • Isolated condition with known/suspected genetic basis • Family history

  8. Why is it important to make a diagnosis? • Cure? …. No • Prognosis • Management • Recurrence risk counseling • Access support groups • Treatment • ‘Why’

  9. How to identify a genetic syndrome • Look for other problems in patient and family members • Major and minor anomalies • Both similar and seemingly unrelated Geneticists’ tools • Personal and family history, and dysmorphologic physical exam • Focusing on minor anomalies

  10. M I N O R A N O M A L I E S From: ‘The child with multiple birth defects’, 2nd ED; MM Cohen Jr

  11. “The best clues are the rarest… (T)hese are not the most obvious anomalies nor even the ones that have the greatest significance for the patient’s health. “ -John Aase, M.D.

  12. References • Smith’s Recognizable Patterns of Human Malformation, 5th edition. KL Jones ed, WB Saunders, 1997. • Syndromes of the Head and Neck, Gorlin, Cohen, eds Oxford Univ Press, 2002 • OMIM (www3.ncbi.nlm.nih.gov/) • GenReviews & GeneTests (www.geneclinics.org)

  13. Birth defects • 1-3% of all newborns • Leading cause of neonatal morbidity and mortality • 20% infant deaths • 10% NICU admissions, 25-35% deaths • Pediatric Admissions • 50% have genetic component to illness • 25-30% have major birth defect

  14. Types of birth defects • Deformation • Disruption • Dysplasia • Malformation

  15. Deformation • Developmental process is normal • Mechanical force alters structure • External • low amniotic fluid, breech presentation • Internal • neuromuscular abnormality development structure

  16. development structure Disruption Interruptionof normal development • usually vascular • example: amniotic band sequence, maternal cocaine use (?)

  17. Amniotic band sequence • Defects do not follow anatomic lines • Asymmetry From: ‘The child with multiple birth defects’, 2nd ED; MM Cohen Jr

  18. Dysplasia • Anomaly of specific type of tissue • Skeletal dysplasia • Osteogenesis Imperfecta, Achondroplasia, Cleidocranial dysplasia • Connective tissue disorder • Marfan syndrome, EhlerDanlos syndrome

  19. Malformation • Developmental process is abnormal • Possible causes • mutant gene(s) • teratogen • stochastic development structure

  20. Causes CLP • Mutant gene(s) • IRF6, MSX1, PVL22, FGFR1 • Teratogen • smoking, alcohol, folate deficiency • Stochastic

  21. Patterns of birth defects • Syndrome:A recognizable pattern of anomalies that are pathogenetically related. • Sequence • Association

  22. Prevalence: 1/5000-20,000 Complete penetrance Inter > intrafamilial variability Pleiotropic long bone overgrowth, joint laxity, eye, & cardiac Diagnosis is clinical, based on established diagnostic criteria requires 2 criteria, plus some involvement of third Genetic testing expensive, not very sensitive, and not clinically useful in most cases Marfan syndrome

  23. Cardiovascular: dilated aortic root w/ AI; cystic medial necrosis with dissection 2. Skeletal (need at least 4) severe pectus carinatum/excavatum decreased upper/lower seg or increased arm span/ height >1.05 thumb & wrist sign; scoliosis per planus (flat feet) protrusio acetabulae (inward protrusion of hip joint by X-ray) Diagnostic criteria Requires 2 criteria plus some involvement of third

  24. 3. Ocular: dislocated lens 4. Family history: independent diagnosis in 1st degree relative Other: dural ectasia, recurrent/incisional hernia, stretch marks, spontaneous pneumothorax, apical blebs, myopia, MVP w/ MR, joint laxity; mild-mod pectus, scoliosis, high arched palate, dental crowding, typical facies (dolichocephaly, malar flatening, deep set eyes, retrognathia, downslanting palpebral fissures) Diagnostic criteria, cont. Requires 2 criteria plus some involvement of third

  25. Marfan syndrome: genetics • Marfan syndrome due to mutations in Fibrillin 1 gene on chromosome 15q21.1 • Large gene, mutations spread out • Most mutations are loss of function & null, some dominant negative • Testing identifies ~90% • Location of mutation does not predict phenotype • correlation of mutation & phenotype very limited • severe/neonatal Marfan syndrome does cluster

  26. Genetic testing for Marfan syndrome • Clinical utility of genetic testing • Positive test confirms diagnosis • Negative test -> other genes (TGFBR1/2, ACTA2, MYH11), disorders • Differential diagnosis • Homocystinuria • similar body habitus, lens dislocation (down vs. up) • differences: stiff joints, malar rash, mental retardation • Congenital contracturalarachnodactyly (Beals syndrome) • ‘Partial’ Marfan Syndrome • Label is not important - manage what you see

  27. Osteogenesis Imperfecta • AD (most) skeletal dysplasia • Easy fracturing + other connective tissue findings • 7+ overlapping subtypes • Type 1: Normal stature, little/no deformity; blue sclerae; 50% HL, DI rare • Type 2: Perinatal lethal; minimal skeletal ossification, beaded ribs, platyspondyly • Type 3: Progressive deforming; short stature; sclerae blue, lighten with age; DI, HL common • Type 4: Variable/mild deformity & short stature; normal sclerae, DI common, some with HL • OI incidence (all types): 1/20,000 • Most due to mutations in type I collagen • Collagen I: 2x COL1A1, 1x COL1A2

  28. Osteogenesis Imperfecta Wormian bones Blue sclerae Femur fracture Intra-uterine fracture

  29. Patterns of birth defects • Syndrome • Sequence: A series of abnormalities derived from a single pathogenetic event. • Association

  30. Pierre Robin sequence • Micrognathia, [U-shaped] cleft palate, glossoptosis • 50% syndromic • Stickler (50%), • del22q11 (25%) • Treacher Collins, Rib gap... Micrognathia ---> cleft palate ---> glossoptosis

  31. Stickler Syndrome • Described in 1965 in 5 generation kindred with AD transmission • Major clinical manifestations: • Myopia, retinal changes • Early/progressive arthritis , mild SED • Sensorineural hearing loss • Cleft palate/Pierre Robin sequence • Marshall, Wagner syndromes

  32. Stickler syndrome genes • AD: COL2A1, COL11A1, COL11A2 • Type II collagen: COL2A1 x 3 • Expressed in joints, inner ear, eye • Type XI collagen: 1 x COL2A1, 1 x COL11A1, 1 x COL11A2 • Same expression pattern as type 2 collagen: except in eye (COL11A2 replaced by COL5A1) • AR: COL9A1, COL9A2

  33. Patterns of birth defects • Syndrome • Sequence • Association: A constellation of findings that occur more commonly together than would be expected by chance alone.

  34. Associations CHARGE Coloboma Heart defect Atresia choani Retarded growth and development Genital anomalies Ear anomalies/ deafness VA(C)TER(L) Vertebral defects Anus, imperforate Cardiac defects T-E fistula Renal Limb (Hydrocephalus)

  35. Associations CHARGE Coloboma Heart defect Atresia choani Retarded growth and development Genital anomalies Ear anomalies/ deafness VA(C)TER(L) Vertebral defects Anus, imperforate Cardiac defects T-E fistula Renal Limb (Hydrocephalus)

  36. CHARGE syndrome • Using comparitive genome hybridization (CGH), deletions on 8q12 was identified in a CHARGE patient • Genes sequenced in minimally deleted region • 10/17 CHARGE patients had mutations in new gene CHD7 • No phenotypic difference between deleted and non-deleted patients

  37. Etiology of syndromes • Chromosomal • Cytogenetic • FISH • Array CGH • Multifactorial • Genes & environment • Environmental • Teratogens, chance • Multiple genes • digenic • Single gene • Autosomal dominant • Autosomal recessive • X-linked • Non-traditional • mitochondrial • imprinting/UPD • triplet repeat

  38. Common Chromosomal Anomalies • Trisomy 21 • Trisomy 18 • Trisomy 13 • XXY • 45X and variants

  39. Down Syndrome

  40. Down Syndrome • “They have considerable power of imitation, even bordering on being mimics. They are humorous, and a lively sense of the ridiculous often colour their mimicry. This faculty of imitation may be cultivated to a very great extent, and a practical direction given to the results obtained. They are usually able to speak; the speech is thick and indistinct, but may be improved very greatly by a well-directed scheme of tongue gymnastics. The coordinating faculty is abnormal, but not so defective that it cannot be greatly strengthened. By systematic training, considerable manipulative power may be obtained. “

  41. Down Syndrome • Down syndrome • Most common malformation pattern ~1 in 800 • Due to extra chromosome 21 material • ‘critical’ region 21q22.3 5 Mb • between D21S58 and D21S42. • Non-disjunction trisomy 94% • 85% due to maternal non-disjunction in Meiosis I • Trisomy with some mosaicism: 2.4% • Translocation (D/G or G/G) 3.3% • Quad Screen result:

  42. Down Syndrome • Diagnosis in an infant: • Flat facial profile 90% • Poor Moro Reflex 85% • Hypotonia 80% • Hyperflexibility of joints 80% • Excess skin on back of neck 80% • Slanted palpebral fissures 80% • Dysplasia of Pelvis 70% • Anomalous auricles 60% • Dysplasia midphalanx 5th finger 60% • Single Palmar creases 45%

  43. Down Syndrome Single Palmar Crease • (NOT simian crease) Sandal Gap

  44. Down Syndrome

  45. Down Syndrome • Problems as they age • Obesity • Loss of hearing • Increasing incidence of hypothyroidism • Celiac Disease • Diminished function • Mental illness – up to 30% • Depression, obsessive-compulsive disorder • Mislabeled as Alzheimer disease

  46. Trisomy 18

  47. Trisomy 18 • Incidence: 3/1000 • More males than females • Shortened life expectancy • About half die in the first month of life • 90% die by the first year of life • Characteristic findings: • Small for gestational age (beware sono EDC) • Short Sternum • “Trisomy 18 clenched hand”

  48. Trisomy 18 Continued … • Multiple organ system involvement • Cardiovascular (VSD, ASD, PDA) • Neuro: Weak, polyhydramnios, hypertonic • GI: TracheoEsophageal fistula OK to repair (?) • Mosaicism and partial Trisomy 18 • Milder phenotype, longer survival • Cause of death • Reported as central apnea (?monitor at home)

  49. Trisomy 13

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