Dataset Information

Whole Genome Sequencing Expands Diagnostic Utility and Improves Clinical Management in Pediatric Medicine.

ABSTRACT: The standard of care for first-tier clinical investigation of the etiology of congenital malformations and neurodevelopmental disorders is chromosome microarray analysis (CMA) for copy number variations (CNVs), often followed by gene(s)-specific sequencing searching for smaller insertion-deletions (indels) and single nucleotide variant (SNV) mutations. Whole genome sequencing (WGS) has the potential to capture all classes of genetic variation in one experiment; however, the diagnostic yield for mutation detection of WGS compared to CMA, and other tests, needs to be established. In a prospective study we utilized WGS and comprehensive medical annotation to assess 100 patients referred to a paediatric genetics service and compared the diagnostic yield versus standard genetic testing. WGS identified genetic variants meeting clinical diagnostic criteria in 34% of cases, representing a 4-fold increase in diagnostic rate over CMA (8%) (p-value = 1.42e-05) alone and >2-fold increase in CMA plus targeted gene sequencing (13%) (p-value = 0.0009). WGS identified all rare clinically significant CNVs that were detected by CMA. In 26 patients, WGS revealed indel and missense mutations presenting in a dominant (63%) or a recessive (37%) manner. We found four subjects with mutations in at least two genes associated with distinct genetic disorders, including two cases harboring a pathogenic CNV and SNV. When considering medically actionable secondary findings in addition to primary WGS findings, 38% of patients would benefit from genetic counseling. Clinical implementation of WGS as a primary test will provide a higher diagnostic yield than conventional genetic testing and potentially reduce the time required to reach a genetic diagnosis.

SUBMITTER: Stavropoulos DJ

PROVIDER: S-EPMC5447450 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Whole Genome Sequencing Expands Diagnostic Utility and Improves Clinical Management in Pediatric Medicine.

Stavropoulos Dimitri J DJ Merico Daniele D Jobling Rebekah R Bowdin Sarah S Monfared Nasim N Thiruvahindrapuram Bhooma B Nalpathamkalam Thomas T Pellecchia Giovanna G Yuen Ryan K C RKC Szego Michael J MJ Hayeems Robin Z RZ Shaul Randi Zlotnik RZ Brudno Michael M Girdea Marta M Frey Brendan B Alipanahi Babak B Ahmed Sohnee S Babul-Hirji Riyana R Porras Ramses Badilla RB Carter Melissa T MT Chad Lauren L Chaudhry Ayeshah A Chitayat David D Doust Soghra Jougheh SJ Cytrynbaum Cheryl C Dupuis Lucie L Ejaz Resham R Fishman Leona L Guerin Andrea A Hashemi Bita B Helal Mayada M Hewson Stacy S Inbar-Feigenberg Michal M Kannu Peter P Karp Natalya N Kim Raymond R Kronick Jonathan J Liston Eriskay E MacDonald Heather H Mercimek-Mahmutoglu Saadet S Mendoza-Londono Roberto R Nasr Enas E Nimmo Graeme G Parkinson Nicole N Quercia Nada N Raiman Julian J Roifman Maian M Schulze Andreas A Shugar Andrea A Shuman Cheryl C Sinajon Pierre P Siriwardena Komudi K Weksberg Rosanna R Yoon Grace G Carew Chris C Erickson Raith R Leach Richard A RA Klein Robert R Ray Peter N PN Meyn M Stephen MS Scherer Stephen W SW Cohn Ronald D RD Marshall Christian R CR

NPJ genomic medicine 20160101

The standard of care for first-tier clinical investigation of the etiology of congenital malformations and neurodevelopmental disorders is chromosome microarray analysis (CMA) for copy number variations (CNVs), often followed by gene(s)-specific sequencing searching for smaller insertion-deletions (indels) and single nucleotide variant (SNV) mutations. Whole genome sequencing (WGS) has the potential to capture all classes of genetic variation in one experiment; however, the diagnostic yield for ...[more]

PMID: 28567303

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Project description:ImportanceEpilepsy is the most common neurological disorder of childhood. Identifying genetic diagnoses underlying epilepsy is critical to developing effective therapies and improving outcomes. Most children with non-acquired (unexplained) epilepsy remain genetically unsolved, and the utility of genome sequencing after nondiagnostic exome sequencing is unknown.ObjectiveTo determine the diagnostic (primary) and clinical (secondary) utility of genome sequencing after nondiagnostic exome sequencing in individuals with unexplained pediatric epilepsy.DesignThis cohort study performed genome sequencing and comprehensive analyses for 125 participants and available biological parents enrolled from August 2018 to May 2023, with data analysis through April 2024 and clinical return of diagnostic and likely diagnostic genetic findings. Clinical utility was evaluated.SettingPediatric referral center.ParticipantsParticipants with unexplained pediatric epilepsy and previous nondiagnostic exome sequencing; biological parents when available.ExposuresShort-read genome sequencing and analysis.Main outcomes and measuresPrimary outcome measures were the diagnostic yield of genome sequencing, defined as the percentage of participants receiving a diagnostic or likely diagnostic genetic finding, and the unique diagnostic yield of genome sequencing, defined as the percentage of participants receiving a diagnostic or likely diagnostic genetic finding that required genome sequencing. The secondary outcome measure was clinical utility of genome sequencing, defined as impact on evaluation, treatment, or prognosis for the participant or their family.Results125 participants (58 [46%] female) were enrolled with median age at seizure onset 3 [IQR 1.25, 8] years, including 44 (35%) with developmental and epileptic encephalopathies. The diagnostic yield of genome sequencing was 7.2% (9/125), with diagnostic genetic findings in five cases and likely diagnostic genetic findings in four cases. Among the solved cases, 7/9 (78%) required genome sequencing for variant detection (small copy number variant, three noncoding variants, and three difficult to sequence small coding variants), for a unique diagnostic yield of genome sequencing of 5.6% (7/125). Clinical utility was documented for 4/9 solved cases (44%).Conclusions and relevanceThese findings suggest that genome sequencing can have diagnostic and clinical utility after nondiagnostic exome sequencing and should be considered for patients with unexplained pediatric epilepsy.

Dataset Information

Whole Genome Sequencing Expands Diagnostic Utility and Improves Clinical Management in Pediatric Medicine.

Publications

Whole Genome Sequencing Expands Diagnostic Utility and Improves Clinical Management in Pediatric Medicine.

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