What s the Human Genome Project Got to Do with Developmental Disabilities? Disclosures Neither speaker has anything to disclose. Phase Two: Interpretation Officially started in October 1990 Goals of the project: Complete sequence of the ~3 billion base pairs of DNA Identify protein-coding genes Make information accessible for research Completed in 2003 Initial results from just 4 people
Human Genome Project Total number of genes = ~20,000 Precise locations on chromosomes now known Junk DNA is not all junk Other functional DNA elements found WORK IN PROGRESS Continually being updated Early Genetic Tests for DD Way back when. Chromosomes - Karyotype - Fragile X Biochemical tests (~30 years ago) FISH: An Advance in Testing for DD 25 years ago. FISH Fluorescent in-situ hybridization Sub-microscopic analysis Targeted chromosome testing Deletions/Duplications Etiology identified for some defined genetic syndromes FISH 22q11.2 deletion
A Big Step in Genetic Testing for DD The Technique of Array CGH 10 Chromosome Microarray Analysis (CMA) AKA : microarray; comparative genomic hybridization (CGH); array CGH (acgh); molecular karyotypying; and more Genome-wide DNA probes Identifies COPY NUMBER VARIANTS (CNV) Many NEW disorders discovered Microarray Can Precisely Define Deletions Microarray Improves Diagnostic Yields CMA makes a diagnosis in ~ 15-20% of cases of intellectual disability, autism spectrum disorder, and multiple congenital anomalies. 2-3 times the yield of karyotype In 2010 CMA was recommended as a first-line test for the above indications by specialty groups, replacing karyotype. ISCA Consortium (a cytogenetics group) American College of Medical Genetics
Known Genetic Causes of Intellectual Disability ORDER: Chromosomal microarray With current testing we can identify a genetic cause in ~40-50% of cases of ID. Visible chromosome abnormalities 15% ~ ½ are Down syndrome Submicroscopic gains and losses 15-20% Single gene disorders ~ 5-10% Includes Fragile X, biochemical disorders, known syndromes Known Genetic Causes of Autism Copy number abnormalities (10%) Fragile X (1 5%) MECP2 (4% of females) PTEN (5% with OFC >2.5 SDs) Karyotype (3%) Other (10%) Total 30-40% yield with current testing The Next Big Thing in Genetic Testing Next Generation Sequencing Large-scale DNA sequencing methods New genes implicated in ID and autism. New clinical tests: Large gene panels Whole exome sequencing looks at all proteincoding genes
Insights from Next-Gen Sequencing Research Findings Are Being Quickly Applied Many single genes associated with ID and autism are being identified many hundreds so far. Some are causal, others are risk factors, others await validation. A given gene can be associated with multiple neurodevelopmental disorders ID, autism, epilepsy Large sequencing panels are available: Autism 61 gene panel Intellectual disability 75-92 gene panels for X-linked ID 70 gene panel for autosomal recessive and dominant ID Mitochondrial disorders Panels of 446, 665, >1100 genes Value of a Genetic Diagnosis What s going on? End the diagnostic odyssey Why did this happen? Did I do something wrong? Allay parental guilt/feeling of responsibility Who else needs to know about this? Identify at-risk relatives Could this happen again? Assists with reproductive planning Where can I get help? Helps families identify and receive resources What medical care do I need? What can I expect? Helps clarify prognosis/aids in management A Genetic Diagnosis Can Guide Management Published management guidelines for some conditions Fragile X, Prader-Willi, Down syndrome, others Identifies associated medical risks When a genetic diagnosis is made by microarray, over 1/3 of cases will have actionable clinical features (often previously unsuspected)
Example Demonstrating Clinical Utility A 4 year old boy with developmental delay. No physical findings on exam. Chromosomal microarray analysis Result: A chromosome 17 deletion known to be associated with ID as well as renal abnormalities and early-onset type 2 diabetes. Renal ultrasound showed cysts and collecting system abnormalities, and referral to nephrology was made. Risk of diabetes prompted glucose monitoring. Limitations of Genetic Testing Not all identified changes have known risks Variants of unknown significance (VOUS) Applies to copy number and sequence variants Not all genetic abnormalities are detectable Little data on disease association with newly implicated genes Lack of clinical validity Is it truly the cause? Can it predict the clinical phenotype? The Future of Genetic Testing for DD increased use of microarray increased use of large-scale sequencing whole GENOME sequencing Diagnostic yield WILL continue to improve Cautionary note: As we examine more genes/dna, the potential for misinterpretation also increases. Underscores need for appropriate counseling A Suggested Testing Strategy for Non-Geneticists Our Recommendation Start with: MICROARRAY FRAGILE X Then Refer to GENETICS Positive or VOUS Interpret results and counsel Negative Evaluate and consider further testing