Genetic Eval of MR
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| Developmental Delay | used for children under 5, descriptive term, used until valud IQ can be measured
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| Mental Retardation | Significant sub-average intellectual behavior and deficits in adaptive behavior
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| Etiology | a specific diagnosis that can be translated into useful clinical information for the family, including providing information about prognosis, recurrence risks, and preferred moes of therapy
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| Diagnostic yield | The percentage of time an etiology can be determined utilizing a specific evaluation test or scheme
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| Expanded phenotype | The full range of phenotypes seen with changes in a specific locus (gene), often initially a gene chance associated with a specific sydnrome
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| Rett Syndrome | 1/10,000-1/15,00; Clinical phenotype of progressive autistiform disorder, exclusively in girls (X-Linked dominant with male lethality), severely imparised expressive language, loss of puprose hand skills, repitive hand movements, truncal ataxia, seizures,
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| Rett Syndrome gene | Gene= MECP2, Xp28
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| Phenotype of MECP-2 mutations male | Encephalopathy (static or progressive) may have peculiar silver-grey hair, Angelman, MR
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| Epidemiology... Incidence | Mental Retardation, males 4 times as common as females; neurodevelopmental disabilities
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| Reported emperic recurrence risks for MR | One child affected, negative family history ~5%
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| If the affected child with MR is male, ... | Brother 5-15%, sister 3-5%, all 2-10%
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| If the affect child with MR is female... | Brother 4-10%, Sister 5-8%, and all have a 3-5%
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| Inheritance of MR is.. | polygenic/oligogenic
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| Polygenic inheritance | IQ dispalys all of the traits of polygenic inheritance... distributed in a normative manner; close relationship to parental IQs, quantitative trait, no sexual dimorphism
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| By definition, what % of the general population has an IQ in the MR Range? | 2.5% (SD)
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| FISH | commonly used to determine if portion of chromosome is deleted.
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| MR Syndromes with Available FISH testing | Williams, Angelman, PW, Smith-Magenis, DiGeorge/VCFS, Miller-Dieker
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| Subtelomeric FISH Panel | 40 individual FISH tests specific for subtelomeric regions (does not have 46 probes for acrocentric chromosomes)
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| Subtelomeric rearragements familial implications | Dependent on parental studies, 90% de novo, 10% positive in one parent
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| Genome microarray | Human Whole Genome Array, Large insert clones (BACs), Clones are arrayed in duplicate
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| CGH | Panels can be customized and are constantly evolving, has likely a 15-20% positive rate for MR
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| Gene Sequencing | FISH tests are very helpful in identifying duplication or deletions of specific loci, won't detect small changes, point mutations etc., often the only method to make a diagnosis is to sequence the gene; but that is very expensive and time consuming
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| Automated mutation screening WAVE | show few to no false negatives...
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| Epidiomiology of MR | Male: Female ratio of 4:1, one explanation is X-linked
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| Sample MRX gene panel | ARX, DLG3, FACL4, FTSK1, JARID1c, PQBP1, TM4SF2,ZNF41
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| Tiered/Step-wise evaluations are based upon... | 1. Expected diagnostic yield, 2. Invasiveness of testing 3. Potential of intervention 4. Overall practicality of obtaining tests
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| Step 1 in Evaluation | Clinical Hx (prenatal, perinatal, postnatal including development, growth and behavior)
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| Step 2 in Eval | Family Hx (parental IQs, developmental abnormalities, psychiatric problems, birth defects, pregnancy loss, and other genetic problems)
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| Step 3 in Eval | Physical Examination (growth parameters, including head; major and minor anomalies and malformations, neurologic examination)
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| Importance of the dysmorphology eval | Establishes the diagnosis (62%), contributes to the diagnosis (79%)
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| What can be a significant aid in reaching a diagnosis? | A characteristic personality and behavioral pattern/behavioral phenotype
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| Behavioral phenotypes | Cognitive levels, static versus progressive, autistiform, disordered sleep, speech and language characteristics, self injurious/aggressive behaviors, associated neurosensory conditions
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| How many of all diagnoses can be made by history and physical examination alone? | 1/3rd to 1/2
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| After the physical eval, what comes next? | Referral for ophthalmologic, audiologic, and/or psychometric testing
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| Neuropsychologic testing | Provides information beyond the simple "IQ" testing; gives information about processes, not just outcomes; non-verbal testing component; can't be performed until mid-childhood, positive predictive value for long term neurodevelopmental potential
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| What comes after referrals in the eval? | Diagnostic testing
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| Karyotypes... (high resolution) | Should be done in ALL developmentally delayed individuals without a recognized cause,
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| Reported diagnostic yield of karyotypes | 9-36%
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| Pigmentary changes | -Embryological association of skin and CNS (neuroectoderm), individuals with neurologic disorders and pigmentary abnormalities should have a fibroblast karyotype if the lymphocytic karyotype is normal; biopsy can be from any site +unselected patch of skin
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| Subtelomere/CGH studies | 1. All patients with MR, 10-15% yield as a single test
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| Molecular testing | Non-syndrome MR (Fragile X, MECP-2), XLMR panel is FH indicates, selected tests based on H&P
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| Fragile X Syndrome: Diagnostic testing | -Recommended for all patients with MR, Diagnostic yield of 2%, reported range of 0-20%, regional uneven distribution (?)
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| Cranial Imaging | 30-96% of those with MR have CNS structural abnormalities detectable by imaging
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| Cranial Imaging leads to an etiology in what % of patients? | 4
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| Abnormal head size and neurological findings increased the likelihood of... | detecting abnormalities
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| Dr. Schaefer says to do cranial imaging on... | all patients without a diagnosis
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| Metabolic testing | Yield only 1% or less; only if clinical indicators; targeted testing, not screening; check newborn screening!
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| Identifiable causes of MR | Chromosome abnormalities 25-30%; UNKNOWN 30-50%
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| Diagnoses increase by how much with return visits for repeat history and physical examination? | 5 to 20%
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| What happens when the brain malfunctions? | 1. Cognition (MR), 2. CP (Motor dysfunction) 3. Movement DOs (HD, Ataxias) 4. Paraximsomal events (seizures- episodic discharge), 5. Autism- behavioral problems
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Created by:
KChatham
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