genetics in medicine
DESCRIPTION
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 - PowerPoint PPT PresentationTRANSCRIPT
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Genetics in Medicine
Nathaniel H. Robin, MD
Department of GeneticsUniversity Alabama at Birmingham
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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
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Dysmorphology vs.
Genomic Medicine
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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.
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Family history
5 yr 3 yr 10 mo
28yr 35 yr 28 yr 29 yr 40 yr 2 wks
Breast cancer SIDS
68yr 45 yr 88 yr 87 yrs“female” cancer
MI
MI
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‘Traditional’ geneticsDysmorphology (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
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• 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
Indications for a Genetics Consultation
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Why is it important to make a diagnosis?
• Cure? …. No
• Prognosis• Management• Recurrence risk counseling• Access support groups• Treatment• ‘Why’
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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
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From: ‘The child with multiple birth defects’, 2nd ED; MM Cohen Jr
MINOR
ANOMALIES
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“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.
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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)
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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
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Types of birth defects
• Deformation• Disruption• Dysplasia• Malformation
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Deformation• Developmental process is
normal• Mechanical force alters
structure• External
– low amniotic fluid, breech presentation
• Internal– neuromuscular
abnormalitydevelopment
structure
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Disruption
– usually vascular– example: amniotic
band sequence, maternal cocaine use (?)
developmentstructure
Interruption of normal development
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From: ‘The child with multiple birth defects’, 2nd ED; MM Cohen Jr
Amniotic band sequence
• Defects do not follow anatomic lines
• Asymmetry
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Dysplasia• Anomaly of specific type of tissue
– Skeletal dysplasia • Osteogenesis Imperfecta, Achondroplasia,
Cleidocranial dysplasia
– Connective tissue disorder • Marfan syndrome, Ehler Danlos syndrome
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Malformation
• Possible causes– mutant gene(s)– teratogen– stochastic
• Developmental process is abnormal
developmentstructure
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Causes CLP
• Mutant gene(s)– IRF6, MSX1, PVL22, FGFR1
• Teratogen– smoking, alcohol, folate deficiency
• Stochastic
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Patterns of birth defects
• Syndrome: A recognizable pattern of anomalies that are pathogenetically related.
• Sequence
• Association
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Marfan syndrome• 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
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Diagnostic criteria Requires 2 criteria plus some involvement of third
1. 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)
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Diagnostic criteria, cont. Requires 2 criteria plus some involvement of third
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)
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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
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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 contractural arachnodactyly (Beals syndrome)– ‘Partial’ Marfan Syndrome
• Label is not important - manage what you see
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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
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Osteogenesis Imperfecta
Blue sclerae
Wormian bones
Intra-uterine fractureFemur fracture
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Patterns of birth defects
Syndrome Sequence: A series of abnormalities
derived from a single pathogenetic event. Association
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Pierre Robin sequence
• Micrognathia, [U-shaped] cleft palate, glossoptosis
• 50% syndromic– Stickler (50%), – del22q11 (25%)– Treacher Collins, Rib
gap...
Micrognathia ---> cleft palate ---> glossoptosis
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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
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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
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Patterns of birth defects
Syndrome Sequence Association: A constellation of findings that
occur more commonly together than would be expected by chance alone.
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Associations
CHARGEColobomaHeart defectAtresia choaniRetarded growth and
developmentGenital anomaliesEar anomalies/ deafness
VA(C)TER(L)Vertebral defectsAnus, imperforateCardiac defectsT-E fistulaRenalLimb(Hydrocephalus)
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Associations
CHARGEColobomaHeart defectAtresia choaniRetarded growth and
developmentGenital anomaliesEar anomalies/ deafness
VA(C)TER(L)Vertebral defectsAnus, imperforateCardiac defectsT-E fistulaRenalLimb(Hydrocephalus)
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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
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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
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Common Chromosomal Anomalies
• Trisomy 21• Trisomy 18• Trisomy 13• XXY• 45X and variants
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Down Syndrome
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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. “
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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:
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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%
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Down SyndromeSingle Palmar Crease
– (NOT simian crease)
Sandal Gap
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Down Syndrome
Life Expectancy in Years
0102030405060708090
100
1920 1930 1940 1950 1960 1970 1980 1990 2000 2010
Year
Age Average Population
Cystic Fibrosis
Down Syndrome
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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
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Trisomy 18
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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”
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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)
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Trisomy 13
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Trisomy 13
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Trisomy 13• Incidence about 1/5000 births• Lifespan limited
– Median survival was 7days– About 10% live past 1 year
• Characteristics:– Holoprosencephaly– Hypotelorism sometimes cyclopia
• Retinal dysplasia and colobomata– Cardiac defects in 80%– Polydactyly– Scalp defects– Other multiple system involvement.
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Trisomy 13
• Mosaicism with less severe phenotype• Partial Trisomy 13
– Proximal 13pter – q14: nonspecific with longer lifespan
– Distal 13q14 – qter: resembles classic phenotype.
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Klinefelter syndrome 47, XXY
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47, XXY• Klinefelter syndrome• Incidence about 1/500 males
– More now found earlier in life – some in neonatal period
• Characteristics– Taller than average and expected from parental
heights– Start puberty but do not complete– Small testes and perhaps small penis– Gynecomastia – more than the usual male teen
• obesity
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47, XXY Continued…• Taurodontism (enlarged pulp, thin surface)• Psychosocial difficulties
– Many complete college• Testosterone supplementation
– Timing– Consideration of psychosocial issues
• Breast cancer– 1 in 5000 men which is 20X general population risk
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Turner syndrome
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45, X Turner syndrome
• NOT 45, XO – there is no “O” chromosome• Second most common aneuploidy found in
conceptions (what is the most common?)• Prenatal detection by sonogram
– Lymphedema• Incidence about 1 in 2500 liveborn females• Characteristics: short stature, webbed neck
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Turner syndrome continued…
• Characteristics continued– Long thin hyperconvex deeply imbedded nails– Bicuspid Aortic valve and coarctation of the aorta– Short neck with low hair line or obvious nuchal swelling– Puffy hands and feet– Broad thorax with widely spaced nipples– Some learning difficulties– Amenorrhea primary and secondary – gonadal dysgenesis– Abnormal kidney structure (horseshoe kidney)– Hypothyroidism– Growth hormone therapy
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Microdeletion syndromes
• Velocardiofacial syndrome (del22q11.22)• Williams (7q11)• Smith Magenis (17p11)• Prader-Willi/Angelman (15q11-13)• WAGR (11p13)• Rubinbstein Taybi (16p13) • Miller Dieker (17p13.3)• Neurofibromatosis I
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Fluorescence in situ hybridization (FISH)
Enhanced resolution -> increased ability to detect missing or extra chromosomal material
Chromosome preparation on slide
Denature DNA
Hybridize, wash, and visualizeusing a fluorescent microscope
Chromosomepaint
OR
DNA probe labeled by incorporatingnucleotides with attached fluorescent
dye, and denatured
Centromericprobe
●Locus specific
probe
OR
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Velocardiofacial syndrome (VCFS)• One of a spectrum of syndromes caused by a
deletion of chromosome 22q11.22– DiGeorge syndrome– Isolated conotruncal congenital heart defects– Isolated neonatal hypocalcemia
• Overall incidence: 1/2-4000• Very variable: >180 anomalies described
involving every organ system
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VCFS: Physical Manifestations
• No minimal diagnostic criteria, obligatory or exclusionary findings
• Main clinic manifestations– Characteristic facial appearance– Congenital cardiovascular disease– Speech, cognitive delays– Psychological and behavioral problems
• Nothing excludes diagnosis
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Genetics of del22q11.22
• Deletion 22q11.22 identified– ~88% de novo
• Common deletion ~3MB, some smaller 1.5-2MB; no phenotypic correlation– Flanked by LCR segments
• TBX1: main gene in DGCR– Mouse tbx1 null elicits 22q11 phenotype
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Recurrent microdeletions are due to flanking low copy number repeats
Normal crossing over
Mis-aligned crossing over
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Comparative genome hybridization (CGH)
The main limitation of CGH is the resolution, which is limited to that of the metaphase chromosome, i.e. ~5-10 Mb for most clinical applications
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Test DNA Control DNA
Hybridization
DNA labeling
Wash and scan
Data analysis
1.00.5(loss)
1.5(gain)
Fluorescence ratio(red/green)
Array comparative genome hybridization
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32K BAC tiling path array CGH Chip
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32K BAC array - Whole genome
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32K BAC array CGH – Whole genome
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Pseudo genetic inheritance (phenocopies)
Phenotype CauseTrisomy 18 Valproic acid embryopathyFamilial DiGeorge RetinoidsFamilial MR/dysmorphia Alcoholism, mat. PKUFamilial obesity Eating too much
Multiple affected family members with colon or breast cancer, Alzheimers, coronary artery disease, etc. at older age
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Multifactorial
• Interaction between genetic and epigenetic (environment, stochastic) factors.
• General rules:– more severe, more “genetic” influence
– less frequently affected sex, more “genetic”
• Ex: pyloric stenosis
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Holoprosencephaly: a model for multifactorial inheritance
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An explanation for the variable expression in HPE
• Many single gene mutations cause HPE: SHH, SIX3, ZIC2, TGIF
• But mutation carriers do not ALWAYS have ‘HPE’, only microforms
• Explanations– Digenic inheritance: mutation in SHH and TGIF– Epigenetic modifiers: low cholesterol in mothers of
HPE/SHH