Whole-genome sequencing expands diagnostic utility and improves clinical management in paediatric medicine Academic Article uri icon

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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.

authors

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

publication date

  • November 2016