Whats the Human Genome Project Neither speaker has anything to - PowerPoint PPT Presentation

Disclosures What’s the Human Genome Project Neither speaker has anything to disclose. Got to Do with Developmental Disabilities? 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 FISH: An Advance in Testing for DD Early Genetic Tests for DD Way back when…. 25 years (~30 years ago) ago…. Chromosomes FISH • Fluorescent in-situ hybridization - Karyotype - Fragile X • Sub-microscopic analysis Biochemical tests • 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 Chromosome Microarray Analysis 10 (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 Improves Diagnostic Yields Microarray Can Precisely Define Deletions • 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 • 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 ORDER: syndromes Chromosomal microarray The Next Big Thing in Genetic Testing Known Genetic Causes of Autism • Copy number abnormalities (10%) • Fragile X (1–5%) Next Generation Sequencing • MECP2 (4% of females) • • PTEN (5% with OFC >2.5 SDs) Large-scale DNA sequencing methods • • Karyotype (3%) New genes implicated in ID and autism. • • Other (10%) New clinical tests: � Large gene panels • Total – 30- 40% yield with current testing � Whole exome sequencing – looks at all protein- coding genes

Insights from Next-Gen Sequencing Research Findings Are Being Quickly Applied • Many single genes associated with ID and autism Large sequencing panels are available: • Autism are being identified – many hundreds so far. � Some are causal, others are risk factors, others � 61 gene panel await validation. • Intellectual disability • A given gene can be associated with multiple � 75-92 gene panels for X-linked ID neurodevelopmental disorders – ID, autism, � 70 gene panel for autosomal recessive and epilepsy dominant ID • Mitochondrial disorders � Panels of 446, 665, >1100 genes A Genetic Diagnosis Can Guide Management Value of a Genetic Diagnosis • What’s going on? • Published management guidelines for some � End the diagnostic odyssey • Why did this happen? Did I do something wrong? conditions � Allay parental guilt/feeling of responsibility • Who else needs to know about this? � Fragile X, Prader-Willi, Down syndrome, others • Identifies associated medical risks � Identify at-risk relatives • Could this happen again? – When a genetic diagnosis is made by microarray, � Assists with reproductive planning • Where can I get help? over 1/3 of cases will have actionable clinical features (often previously unsuspected) � Helps families identify and receive resources • What medical care do I need? What can I expect? � Helps clarify prognosis/aids in management

Limitations of Genetic Testing Example Demonstrating Clinical Utility • Not all identified changes have known risks • A 4 year old boy with developmental delay. No � Variants of unknown significance (VOUS) physical findings on exam. � Applies to copy number and sequence variants � Chromosomal microarray analysis • Not all genetic abnormalities are detectable • Result: A chromosome 17 deletion known to be • Little data on disease association with newly associated with ID as well as renal abnormalities implicated genes and early-onset type 2 diabetes. � Lack of clinical validity – Is it truly the cause? Can � Renal ultrasound showed cysts and collecting system it predict the clinical phenotype? abnormalities, and referral to nephrology was made. � Risk of diabetes prompted glucose monitoring. A Suggested Testing Strategy The Future of Genetic Testing for DD for Non-Geneticists …increased use of microarray • Our Recommendation …increased use of large-scale sequencing � Start with: …whole GENOME sequencing • MICROARRAY Diagnostic yield WILL continue to improve • FRAGILE X Cautionary note: As we examine more genes/DNA, the potential for misinterpretation also increases. � Then � Refer to GENETICS • Positive or VOUS – Interpret results and counsel � Underscores need for • Negative – Evaluate and consider further testing appropriate counseling