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Dysmorphology

Genetics and Autism

QuestionAnswer
Intro: Genetics of Autism 1. Undisputable genetic basis 2. complex inheritance 3. etiologic heterogeneity 4. genetic heterogeneity 5. likely environmental modifers
Autism genetics 1. Phenocopies (FraX) 2. Essential versus complex 3. Locus heterogeneity 4. Oligogeneic inheritance 5. Allelic heterogeneity 6. Epigentics 7. Gene-gene interaction 8. Gene-env interaction
Evidences to the genetic basis of autism 1. MF inheritance 2. Concordance data 3. gene studies...
Heritability of autism phenotype h >0.9
Heritability of autism trait in general (non-autistic) poulation h= 0.8
MZ Concordance of Autism 70% (with 80% broader concordance of phenotype)
DZ concordance of autism 3% (range 0-23%) but 26% for broader phenotype
AS/PWS individuals with autism 2-42%
Autism and dups 15q
Reduced in frontal cortex of patients with autism. Correlates with abnormal methylation MECP2
Multifactorial inheritance modes... 1. Lipid metabolism2. thrombosis3. blood pressure4. insulin resistence5. endothelial properties6. Inflammation...All with Atherosclerosis and environmental factors contributing
Overall recurrence risk to sibs with autism 3-9%
If affected child is female, the sib recurrence risk for autism is... 14.5% or 7%
If affected child is male, the sib recurrence risk for autism is... 7% or 4%
If two sibs are affected by autism, recurrence risk to next sib is... 33-50%
Relative recurrence risk for autism 22.3
Relative recurrence risk for Asperger 13.4
Autism is how many times more likely in males? 2-4
Sporadic occurrences associated with autism... Advanced paternal age
Linkage and autism... 2 minor linkages to.. X chromosome
Linkage to most autosomes... 2, 3, 7, 15, 18, 19, x
Most replicated Autism linkage... 7q31-35
Next most common LOD in autism... 2q, 15q
x-linked genes associated with autism NGN3 and NFN4
PTEN is linked to autism when head circumference is... >2.5 above SD
Techniques to identify candidate genes for autism 1. Copy number variants/structural variants (10% of simplex cases) 2. Genome wide association studies 3. piRNA analysis (only in male germline and survey spermatids)
Two types of autism Complex/Syndromic and Essential
Complex Autism 1. 20% of total autism population 2. abnormalities in early morphologenesis manifested by either sig. dysmorphology, a recog. syndrome or microcephaly 3. Poorer outcomes (Lower IQ, more seizures, abnormal EEgs, more abnormal findings)
Essential autism 80% of autism population, more heritable group, more relatives with autism, higher male:female ratio
Chromosome anomalies associated with autism Most commonly seen are 15q proximal deletions or dups
Other common aneuplodies associated with autism 1. deletions of 7q, dups of 22q13, deletions of 2q37, 18q, Xp, and 47XYY; 45,X/46XY
FISH Studies for autism 15q, 22q11, 22q13, 17p, 2q
22q11.2 deletions and autism Minimal to no other phenotypic changes
FISH Studies on subtelomeric FISH panel obsolete
FISH and aCGH studies highly effective tool, CNVs may contribute to 20% of autisms,
FISH and aCGH studies, recently reported that micro-dup/del of... 16p11.2 may be linked with autism
15q and autism 11-13 critical regions for PWS/AS, contains ~50 genes, GABA receptor
Fragile X Syndrome and autism ~20% of patients have autism
What % of Autistic patients have Fragile X? 2-10%
Autistic behaviors often get... better with time
Performance on IQ tests often ... declines with age, not a progressive DO though
There are three fragile sites that tare solate senstive seen in autism. What are they? 1. 2q13 (2. 6p23 (3. 12q13
Pigmentary changes and autism Embryonic association between CNS and neuroectoderm
Rare syndromes and autism 1. Rett Syndrome 2. MECP-2 syndromes 3. Angelman 4. Smith-Magenis 5. Sotos 6. FG
Angelman clinical features 1. Severe MR 2. Periods of unprovoked laughter 3. Absent speech 4. microcephaly 5. autistic behaviors 6. ataxic gait 7. etiology: upd 15q12 or interstititial deletion
Smith-Magenis syndrome 1. MR with autistiform behaviors and mild dysmorphisms. associated with deletion 17p11.2
Smith-Magenis ssyndrome phenotype... Craniofacial features: Broad aquare face, heavy brows, excessive lateral extensions of eyesbrtows, up slanting papebral fissures, deep set-close set eyes, depressed nasal brdige, wide mouth, full lips, everted upper lip with prominent philtral ridges
SM phenotype... behaviors autistiform, agression towards others, self injgurious behaviors, self stimulation, sleep disturbance
Sotos syndrome 1. Facial features with macrocephaly, 2. overgrowth with advanced bone age, developmental delays, especially speech... behavioral features (phobias, obsessions, compulsions, austics behaviors) strong overlap with Fragile X phenotype
Sotos syndrome 90-95% have an abnormality of gene NSD1 (15% detectable by FISH, 75% have point mutations)
FG syndrome wide set eyes, broad nasal brdige, low set simple ears, open-moutehd appearance with thin upper-lip and fuller lower-lip, tongues often protrude slightly from mouths, cowlicks in their hair and widow's peak hairline.
FG syndrome common recognizable features... poor muscle tone, chronic constipation, hearing loss, vision problems, genital abnormalities, respiratory problems... some kids have congenital heart fedects, agenesis of the corpus collosum and or imperforate anus
Individuals with Fg syndrome tend to ... outgoing, talkative, and crave lots of attention
Individuals with Fg syndrome also tend to be very.. gentle spirited and "mellow" but may be easily frustrated and prone to temper tantrums
Bannyan-Riley-Ruvalcaba syndrome PTEN Disorder (10a23.31) allelic to cowden disease
Bannyan-Riley-Ruvalcaba syndrome -Early overgrowth -Cognitive defects - macrocephaly -craniofacial dysmorphisms, cutaneous lesions including penile freackling, tumors, and lipd storage myopathy
Strongest association is between autism and PTEN disorders
Strong association between autism and what ceurocutaneous disorder? TS
TS clinical features 1. AD 2. Pitted dental enamel 3. Cardiac rhabdomyoma 4. re3nal cysts 5. cystic areas of bone rarefaction 6. facial angiofibroma
Common skin findings in individual with TS 1. White ask lead macules, 2. shagreenpatch 3. subcutaneous nodules, 4. subungual fibromata
CNSish features of TS 1. Seizures 2. MR 3. Autistic behaviors 4. Intracranial calficication by x-ray or CT 5.
Mental retardation is seen in what % of patients with NF 3-8%
Speech and language disabilities are seen in what % of patients with NF 30-45%
Problems associated with NF 1. Visual-motor integration 2. Manual dexterity and balance 3. some autistic behaviors 4. No "consistent pattern"
A significant number of patients with autism have... identifiable inborn errors in metabolism
"Classic" metabolic disorders and autism 1. untreated PKU 2. Organic acidemias 3. MPS
MPS clinical features 1. Mild coarse facies 2. Hirsutism 3. Asymmetric septal hypertrophy 4. Frequent Upper respiratory infections 5. dysostosis multiplex 6. mild hepatosplenomegaly 7. hearing loss 8. mr 9. hyperactivity 10. severe autistiform behaviors
MPS and autism... early stages can look like autistic regressive syndrome
SLO 53% of these patients also have autism
SLO face microcephaly, bitemporal narrowing, ptosis, short nasal roots, anteverted nares, and small chin
SLO clinical features cleft palate, polydactyly and syndactyly, genital anomalies, and CNS anomalies
Gentital anomalies seen with SLO hypospadias and cryptorchidism
CNS anomalies 1. Microcephaly 2. Holoprogsencephaly 3. enarlged ventricles 4. absence of the corpus callosum
SLO neurobehaviors 1. Psychomotor retardation (70% or more with sleep cycle disturbances), 2. Hyperactivity 3. Repetitive behavior 4. Autistic 5. Self-injurious 6. infants cry constantly
SLO and autism Greater language expressiveness and receptiveness; "syndromic specific behaviors"
Newer dx associations with autism and metabolic disorders 1. purine metabolism 2. pyrimidine metabolism 3. unknown sulfation defect 6. GABA metabolism 7. Creatine metabolism
Teratogens associated with Autism Congenital rubella is most convincing. Others include: maternal hypothyroidism, volproate, thalidomide, alcohol, CMV
Dx Eval of the autistic patient: Pre-eval History and physical, hearing eval, confirmation by mental health professional, cognitive testing, EEG
Important elements in the Patient Hx: Prenatal Hx Maternal Rubella status, maternal thyroid disease and teratogenic exposures to CMW, alcohol, thalidomide and valproic acid
Important elements in the patient hx: Medical Hx Seizures and/or neuro-regression, acquired aphasia
Important elements in the patient hx: Family Hx Cancer (esp. thyroid), hamartomas of skin, GI tract, CND, eyes and GI tract; congenital anomalies; Xlinked pattern of neurodevelopmental/neurobehavioral disorders
Important clues on the physical exam Head Size, Pigmentary abnormalities, subtle dysmorphis features (lip sneer, syndactyly, retinal changes)
Dx eval of Autism: first tier Dysmorphology exam; metabolic screen and/or rubella titers; chromosomes and fragile X studies; aCGH
Dx eval of Autism: second tier Fibroblast karyotype; MeCP2 for females, PTEN
Dx eval of Autism: third tier Brain MRI; chromosome 15 methylation for PWS/AS; Serum and uric acid
Dx eval of Autism: fourth tier Extended metabolic work-up
What % of autistic kids have a defined etiology? 40-45%
Commonly reported dx yield for autism: 6-15%
Complete neurogenetic eval is recommended for all persons with... ASD
Dx Eval of the autistic patient: Pre-eval History and physical, hearing eval, confirmation by mental health professional, cognitive testing, EEG
Important elements in the Patient Hx: Prenatal Hx Maternal Rubella status, maternal thyroid disease and teratogenic exposures to CMW, alcohol, thalidomide and valproic acid
Important elements in the patient hx: Medical Hx Seizures and/or neuro-regression, acquired aphasia
Important elements in the patient hx: Family Hx Cancer (esp. thyroid), hamartomas of skin, GI tract, CND, eyes and GI tract; congenital anomalies; Xlinked pattern of neurodevelopmental/neurobehavioral disorders
Important clues on the physical exam Head Size, Pigmentary abnormalities, subtle dysmorphis features (lip sneer, syndactyly, retinal changes)
Dx eval of Autism: first tier Dysmorphology exam; metabolic screen and/or rubella titers; chromosomes and fragile X studies; aCGH
Dx eval of Autism: second tier Fibroblast karyotype; MeCP2 for females, PTEN
Dx eval of Autism: third tier Brain MRI; chromosome 15 methylation for PWS/AS; Serum and uric acid
Dx eval of Autism: fourth tier Extended metabolic work-up
What % of autistic kids have a defined etiology? 40-45%
Commonly reported dx yield for autism: 6-15%
Complete neurogenetic eval is recommended for all persons with... ASD
Created by: Kali Chatham Kali Chatham on 2010-05-01



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