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Dysmorphology
Genetics and Autism
| Question | Answer |
|---|---|
| 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:
KChatham
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