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Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test.

ABSTRACT: PurposeGenetic testing is an integral diagnostic component of pediatric medicine. Standard of care is often a time-consuming stepwise approach involving chromosomal microarray analysis and targeted gene sequencing panels, which can be costly and inconclusive. Whole-genome sequencing (WGS) provides a comprehensive testing platform that has the potential to streamline genetic assessments, but there are limited comparative data to guide its clinical use.MethodsWe prospectively recruited 103 patients from pediatric non-genetic subspecialty clinics, each with a clinical phenotype suggestive of an underlying genetic disorder, and compared the diagnostic yield and coverage of WGS with those of conventional genetic testing.ResultsWGS identified diagnostic variants in 41% of individuals, representing a significant increase over conventional testing results (24%; P?=?0.01). Genes clinically sequenced in the cohort (n?=?1,226) were well covered by WGS, with a median exonic coverage of 40 × ±8 × (mean ±SD). All the molecular diagnoses made by conventional methods were captured by WGS. The 18 new diagnoses made with WGS included structural and non-exonic sequence variants not detectable with whole-exome sequencing, and confirmed recent disease associations with the genes PIGG, RNU4ATAC, TRIO, and UNC13A.ConclusionWGS as a primary clinical test provided a higher diagnostic yield than conventional genetic testing in a clinically heterogeneous cohort.

SUBMITTER: Lionel AC

PROVIDER: S-EPMC5895460 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test.

Lionel Anath C AC Costain Gregory G Monfared Nasim N Walker Susan S Reuter Miriam S MS Hosseini S Mohsen SM Thiruvahindrapuram Bhooma B Merico Daniele D Jobling Rebekah R Nalpathamkalam Thomas T Pellecchia Giovanna G Sung Wilson W L WWL Wang Zhuozhi Z Bikangaga Peter P Boelman Cyrus C Carter Melissa T MT Cordeiro Dawn D Cytrynbaum Cheryl C Dell Sharon D SD Dhir Priya P Dowling James J JJ Heon Elise E Hewson Stacy S Hiraki Linda L Inbar-Feigenberg Michal M Klatt Regan R Kronick Jonathan J Laxer Ronald M RM Licht Christoph C MacDonald Heather H Mercimek-Andrews Saadet S Mendoza-Londono Roberto R Piscione Tino T Schneider Rayfel R Schulze Andreas A Silverman Earl E Siriwardena Komudi K Snead O Carter OC Sondheimer Neal N Sutherland Joanne J Vincent Ajoy A Wasserman Jonathan D JD Weksberg Rosanna R Shuman Cheryl C Carew Chris C Szego Michael J MJ Hayeems Robin Z RZ Basran Raveen R Stavropoulos Dimitri J DJ Ray Peter N PN Bowdin Sarah S Meyn M Stephen MS Cohn Ronald D RD Scherer Stephen W SW Marshall Christian R CR

Genetics in medicine : official journal of the American College of Medical Genetics 20170803 4

PurposeGenetic testing is an integral diagnostic component of pediatric medicine. Standard of care is often a time-consuming stepwise approach involving chromosomal microarray analysis and targeted gene sequencing panels, which can be costly and inconclusive. Whole-genome sequencing (WGS) provides a comprehensive testing platform that has the potential to streamline genetic assessments, but there are limited comparative data to guide its clinical use.MethodsWe prospectively recruited 103 patient ...[more]

PMID: 28771251

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Project description:BackgroundAutism spectrum disorder (ASD) affects 1 in 100 children globally with a rapidly increasing prevalence. To the best of our knowledge, no data exists on the genetic architecture of ASD in India. This study aimed to identify the genetic architecture of ASD in India and to assess the use of whole exome sequencing (WES) as a first-tier test instead of chromosomal microarray (CMA) for genetic diagnosis.MethodsBetween 2020 and 2022, 101 patient-parent trios of Indian origin diagnosed with ASD according to the Diagnostic and Statistical Manual, 5th edition, were recruited. All probands underwent a sequential genetic testing pathway consisting of karyotyping, Fragile-X testing (in male probands only), CMA and WES. Candidate variant validation and parental segregation analysis was performed using orthogonal methods.ResultsOf 101 trios, no probands were identified with a gross chromosomal anomaly or Fragile-X. Three (2.9%) and 30 (29.7%) trios received a confirmed genetic diagnosis from CMA and WES, respectively. Amongst diagnosis from WES, SNVs were detected in 27 cases (90%) and CNVs in 3 cases (10%), including the 3 CNVs detected from CMA. Segregation analysis showed 66.6% (n = 3 for CNVs and n = 17 for SNVs) and 16.6% (n = 5) of the cases had de novo and recessive variants respectively, which is in concordance with the distribution of variant types and mode of inheritance observed in ASD patients of non-Hispanic white/ European ethnicity. MECP2 gene was the most recurrently mutated gene (n = 6; 20%) in the present cohort. Majority of the affected genes identified in the study cohort are involved in synaptic formation, transcription and its regulation, ubiquitination and chromatin remodeling.ConclusionsOur study suggests de novo variants as a major cause of ASD in the Indian population, with Rett syndrome as the most commonly detected disorder. Furthermore, we provide evidence of a significant difference in the diagnostic yield between CMA (3%) and WES (30%) which supports the implementation of WES as a first-tier test for genetic diagnosis of ASD in India.

Dataset Information

Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test.

Publications

Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test.

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