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Exome Sequencing Is a First-Tier Clinical Diagnostic Test for Individuals with Neurodevelopmental Disorders

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Exome Sequencing Is a First-Tier Clinical Diagnostic Test for Individuals with Neurodevelopmental Disorders SYSTEMATIC REVIEW Meta-analysis and multidisciplinary consensus statement: exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders Siddharth Srivastava, MD1, Jamie A. Love-Nichols, MS, MPH 1, Kira A. Dies, ScM1, David H. Ledbetter, PhD 2, Christa L. Martin, PhD2, Wendy K. Chung, MD, PhD3,4, Helen V. Firth, DM, FRCP5,6, Thomas Frazier, PhD7, Robin L. Hansen, MD8, Lisa Prock, MD, MPH1,9, Han Brunner, MD10,11,12, Ny Hoang, MS13,14,15, Stephen W. Scherer, PhD 14,15,16,17, Mustafa Sahin, MD PhD 1, David T. Miller, MD PhD 18 and the NDD Exome Scoping Review Work Group Purpose: For neurodevelopmental disorders (NDDs), etiological individuals with isolated NDD, or NDD plus associated conditions evaluation can be a diagnostic odyssey involving numerous genetic (such as Rett-like features). Yield of ES was 36% overall, 31% for tests, underscoring the need to develop a streamlined algorithm isolated NDD, and 53% for the NDD plus associated conditions. ES maximizing molecular diagnostic yield for this clinical indication. yield for NDDs is markedly greater than previous studies of CMA Our objective was to compare the yield of exome sequencing (ES) (15–20%). with that of chromosomal microarray (CMA), the current first-tier Conclusion: Our review demonstrates that ES consistently test for NDDs. outperforms CMA for evaluation of unexplained NDDs. We Methods: We performed a PubMed scoping review and meta- propose a diagnostic algorithm placing ES at the beginning of the analysis investigating the diagnostic yield of ES for NDDs as the evaluation of unexplained NDDs. basis of a consensus development conference. We defined NDD as global developmental delay, intellectual disability, and/or autism Genetics in Medicine (2019) 21:2413–2421; https://doi.org/10.1038/s41436- spectrum disorder. The consensus development conference 019-0554-6 included input from genetics professionals, pediatric neurologists, and developmental behavioral pediatricians. Keywords: autism; consensus development conference; diagnos- Results: After applying strict inclusion/exclusion criteria, we tic yield; genetic testing; intellectual disability identified 30 articles with data on molecular diagnostic yield in INTRODUCTION College of Medical Genetics and Genomics (ACMG) suggests Neurodevelopmental disorders (NDDs) are a heterogeneous that chromosomal microarray (CMA) and fragile X (FXS) group of conditions that impact brain development and affect testing should be first-tier tests for individuals with various aspects of daily functioning. At least 30% of NDDs are unexplained GDD/ID and/or ASD (except for females with thought to have a genetic basis.1 Among these disorders, ASD and normal cognition, for which FXS testing is not global developmental delay (GDD)—a precursor diagnosis to recommended).3 There are also considerations for single-gene intellectual disability (ID)—and autism spectrum disorder testing of MECP2 and PTEN under certain circumstances,2 (ASD) are two entities for which there are guidelines for although gene panels are now typically preferred over single- genetic testing.2,3 The 2010 guideline from the American gene testing. These recommendations and practices exist 1Translational Neuroscience Center, Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA; 2Autism & Developmental Medicine Institute, Geisinger, Danville, PA, USA; 3Departments of Pediatrics and Medicine, Columbia University, New York, NY, USA; 4SFARI, Simons Foundation, New York, NY, USA; 5Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK; 6East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK; 7Autism Speaks, Cleveland, OH, USA; 8MIND Institute, Department of Pediatrics, University of California Davis, Sacramento, CA, USA; 9Developmental Medicine Center, Boston Children’s Hospital, Boston, MA, USA; 10Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; 11Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands; 12The Netherlands; Department of Clinical Genetics and GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands; 13Department of Genetic Counselling, The Hospital for Sick Children, Toronto, ON, Canada; 14Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada; 15Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; 16The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada; 17McLaughlin Centre and Department of Molecular Genetics, Faculty of Medicine, University of Toronto, Toronto, ON, Canada; 18Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA, USA. Correspondence: Mustafa Sahin ([email protected]) These authors contributed equally: Siddharth Srivastava, Jamie A. Love-Nichols. Submitted 20 February 2019; accepted: 15 May 2019 Published online: 11 June 2019 GENETICS in MEDICINE | Volume 21 | Number 11 | November 2019 2413 SYSTEMATIC REVIEW SRIVASTAVA et al because of the complex genetic heterogeneity underlying Table 1 Types of genetic variants detected and missed by NDDs that sometimes makes diagnostic determinations CMA and ES 4 difficult based on history/examination alone. Even when Test Types of variants detected Types of variants missed following these guidelines, establishing a diagnosis can require CMA Chromosomal copy-number Balanced chromosomal iterative genetic testing. Previous expert guidance on genetic variants (deletions and rearrangements testing for NDDs has advanced testing as standard of care for duplications) at the level of Low-level mosaicism individuals with NDDs.2,5 Such guidelines also predate the intragenic exons or larger Trinucleotide repeat expansion rapid uptake of clinical exome sequencing (ES) and therefore disorders (e.g., fragile X ES is not addressed. syndrome) Due to the genetic heterogeneity of NDDs, and the current Single-gene sequence-level standard of genome-wide CMA as the first-tier test, we variants found by ES focused on ES in comparison with CMA because it also ES Single-gene variants Chromosomal copy-number provides a genome-wide assessment. The advent of ES has variants (except when elucidated monogenic forms of GDD/ID and/or ASD not specifically included in analysis detectable by CMA, FXS testing, or single-gene sequencing of pipeline) MECP2 or PTEN.4,6 For individuals with GDD/ID, ASD, and/ Balanced chromosomal or multiple congenital anomalies (MCAs), the molecular rearrangements diagnostic yield of CMA is up to 15–20% (ref. 5), including – Trinucleotide repeat expansion more recent cohorts.7 9 CMA typically detects only chromo- disorders somal copy-number variants (CNVs) and regions of homo- Intronic/noncoding variants zygosity, not single-gene disorders10 (Table 1). Several ES Exon-level deletions/ 1234567890():,; studies have focused on individuals with varying presenta- duplications tions of NDDs and have identified genetic causes in as many Exonic variants not captured or as 61% of cases.1,11,12 covered well by sequencing Much like CMA, ES is useful for patients with atypical platform presentations of a genetic disorder, early presentations of a CMA chromosomal microarray, ES exome sequencing. disease for which the classic findings have not appeared, genetic disorders with relatively nonspecific presentations, and multiple genetic conditions. One of the main historical MATERIALS AND METHODS limitations of ES was lack of detection of CNVs (Table 1), We conducted a scoping review (no registered review though advances in depth-of-sequence coverage analysis and protocol) as the basis for a consensus development conference of apparent Mendelian segregation errors can afford detection to summarize the molecular diagnostic yield of ES for NDDs, of CNVs from ES.13 With these advances, some clinical specifically compared with CMA. For the conference, in laboratories have started to incorporate CNV analysis into addition to the core group of experts who authored this paper, their ES platforms. we also invited outside experts on CNV analysis from ES data. The value of elucidating a molecular diagnosis is that it can change clinical management in a number of important ways Scoping review for individuals and families affected by a NDD. Several For this scoping review, we addressed the following question: studies have examined the impact of a diagnostic CMA Among individuals with NDDs tested by ES, what is the finding, showing that it leads to direct changes in patient care molecular diagnostic yield compared with CMA? We selected – for up to 55% of individuals with a positive result.14 17 articles from PubMed focusing on ES and NDDs. We Similarly, a diagnosis via ES can impact patient care by included studies that involved sequencing of protein-coding initiation of surveillance for disease-related conditions, regions of Mendelian genes, and excluded studies that were discontinuation of repeated rounds of investigation and gene panels subsampled from exome data. We defined NDD irrelevant surveillance, and referrals for further evaluation of as GDD, ID, and/or ASD. We searched PubMed with a associated medical conditions.18 Despite the clear benefit of combination of Medical Subject Headings (MeSH) terms and ES from a diagnostic and management standpoint, there are keywords pertaining to
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