OBJECTIVE: Epilepsy is highly prevalent among patients with intellectual disability (ID), and seizure control is often difficult. Identification of the underlying etiology in this patient group is important for daily clinical care. We assessed the diagnostic yield of whole exome sequencing (WES). In addition, we evaluated which clinical characteristics influence the likelihood of identifying a genetic cause and we assessed the potential impact of the genetic diagnosis on (antiepileptic) treatment strategy. METHODS: One hundred patients with both unexplained epilepsy and (borderline) ID (intelligence quotient ≤ 85) were included. All patients were evaluated by a clinical geneticist, a (pediatric) neurologist, and/or a specialist ID physician. WES analysis was performed in two steps. In step 1, analysis was restricted to the latest versions of ID and/or epilepsy gene panels. In step 2, exome analysis was extended to all genes (so-called full exome analysis). The results were classified according to the American College of Medical Genetics and Genomics guidelines. RESULTS: In 58 patients, the diagnostic WES analysis reported one or more variant(s). In 25 of the 100 patients, these were classified as (likely) pathogenic, in 24 patients as variants of uncertain significance, and in the remaining patients the variant was most likely not related to the phenotype. In 10 of 25 patients (40%) with a (likely) pathogenic variant, the genetic diagnosis might have an impact on the treatment strategy in the future. SIGNIFICANCE: This study illustrates the clinical diagnostic relevance of WES for patients with both epilepsy and ID. It also demonstrates that implementing WES diagnostics might have impact on the (antiepileptic) treatment strategy in this population. Confirmation of variants of uncertain significance in (candidate) genes may further increase the yield. Wiley Periodicals, Inc.
OBJECTIVE:Epilepsy is highly prevalent among patients with intellectual disability (ID), and seizure control is often difficult. Identification of the underlying etiology in this patient group is important for daily clinical care. We assessed the diagnostic yield of whole exome sequencing (WES). In addition, we evaluated which clinical characteristics influence the likelihood of identifying a genetic cause and we assessed the potential impact of the genetic diagnosis on (antiepileptic) treatment strategy. METHODS: One hundred patients with both unexplained epilepsy and (borderline) ID (intelligence quotient ≤ 85) were included. All patients were evaluated by a clinical geneticist, a (pediatric) neurologist, and/or a specialist ID physician. WES analysis was performed in two steps. In step 1, analysis was restricted to the latest versions of ID and/or epilepsy gene panels. In step 2, exome analysis was extended to all genes (so-called full exome analysis). The results were classified according to the American College of Medical Genetics and Genomics guidelines. RESULTS: In 58 patients, the diagnostic WES analysis reported one or more variant(s). In 25 of the 100 patients, these were classified as (likely) pathogenic, in 24 patients as variants of uncertain significance, and in the remaining patients the variant was most likely not related to the phenotype. In 10 of 25 patients (40%) with a (likely) pathogenic variant, the genetic diagnosis might have an impact on the treatment strategy in the future. SIGNIFICANCE: This study illustrates the clinical diagnostic relevance of WES for patients with both epilepsy and ID. It also demonstrates that implementing WES diagnostics might have impact on the (antiepileptic) treatment strategy in this population. Confirmation of variants of uncertain significance in (candidate) genes may further increase the yield. Wiley Periodicals, Inc.
Authors: Kimberly A Aldinger; Andrew E Timms; Zachary Thomson; Ghayda M Mirzaa; James T Bennett; Alexander B Rosenberg; Charles M Roco; Matthew Hirano; Fatima Abidi; Parthiv Haldipur; Chi V Cheng; Sarah Collins; Kaylee Park; Jordan Zeiger; Lynne M Overmann; Fowzan S Alkuraya; Leslie G Biesecker; Stephen R Braddock; Sara Cathey; Megan T Cho; Brian H Y Chung; David B Everman; Yuri A Zarate; Julie R Jones; Charles E Schwartz; Amy Goldstein; Robert J Hopkin; Ian D Krantz; Roger L Ladda; Kathleen A Leppig; Barbara C McGillivray; Susan Sell; Katherine Wusik; Joseph G Gleeson; Deborah A Nickerson; Michael J Bamshad; Dianne Gerrelli; Steven N Lisgo; Georg Seelig; Gisele E Ishak; A James Barkovich; Cynthia J Curry; Ian A Glass; Kathleen J Millen; Dan Doherty; William B Dobyns Journal: Am J Hum Genet Date: 2019-08-29 Impact factor: 11.025
Authors: Morgan N Similuk; Jia Yan; Rajarshi Ghosh; Andrew J Oler; Luis M Franco; Michael R Setzer; Michael Kamen; Colleen Jodarski; Thomas DiMaggio; Joie Davis; Rachel Gore; Leila Jamal; Adrienne Borges; Nicole Gentile; Julie Niemela; Chenery Lowe; Kathleen Jevtich; Yunting Yu; Haley Hullfish; Amy P Hsu; Celine Hong; Patricia Littel; Bryce A Seifert; Joshua Milner; Jennifer J Johnston; Xi Cheng; Zhiwen Li; Daniel Veltri; Ke Huang; Krishnaveni Kaladi; Jason Barnett; Lingwen Zhang; Nikita Vlasenko; Yongjie Fan; Eric Karlins; Satishkumar Ranganathan Ganakammal; Robert Gilmore; Emily Tran; Alvin Yun; Joseph Mackey; Svetlana Yazhuk; Justin Lack; Vasudev Kuram; Wenjia Cao; Susan Huse; Karen Frank; Gary Fahle; Sergio Rosenzweig; Yan Su; SuJin Hwang; Weimin Bi; John Bennett; Ian A Myles; Suk See De Ravin; Ivan Fuss; Warren Strober; Bibiana Bielekova; Adriana Almeida de Jesus; Raphaela Goldbach-Mansky; Peter Williamson; Kelly Kumar; Caeden Dempsy; Pamela Frischmeyer-Guerrerio; Robin Fisch; Hyejeong Bolan; Dean D Metcalfe; Hirsh Komarow; Melody Carter; Kirk M Druey; Irini Sereti; Lesia Dropulic; Amy D Klion; Paneez Khoury; Elise M O' Connell; Nicole C Holland-Thomas; Thomas Brown; David H McDermott; Philip M Murphy; Vanessa Bundy; Michael D Keller; Christine Peng; Helen Kim; Stephanie Norman; Ottavia M Delmonte; Elizabeth Kang; Helen C Su; Harry Malech; Alexandra Freeman; Christa Zerbe; Gulbu Uzel; Jenna R E Bergerson; V Koneti Rao; Kenneth N Olivier; Jonathan J Lyons; Andrea Lisco; Jeffrey I Cohen; Michail S Lionakis; Leslie G Biesecker; Sandhya Xirasagar; Luigi D Notarangelo; Steven M Holland; Magdalena A Walkiewicz Journal: J Allergy Clin Immunol Date: 2022-06-24 Impact factor: 14.290
Authors: Sathiya N Manivannan; Jolien Roovers; Noor Smal; Candace T Myers; Dilsad Turkdogan; Filip Roelens; Oguz Kanca; Hyung-Lok Chung; Tasja Scholz; Katharina Hermann; Tatjana Bierhals; Hande S Caglayan; Hannah Stamberger; Heather Mefford; Peter de Jonghe; Shinya Yamamoto; Sarah Weckhuysen; Hugo J Bellen Journal: Brain Date: 2022-06-03 Impact factor: 15.255
Authors: Norman Delanty; Gianpiero L Cavalleri; Katherine A Benson; Maire White; Nicholas M Allen; Susan Byrne; Robert Carton; Elizabeth Comerford; Daniel Costello; Colin Doherty; Brendan Dunleavey; Hany El-Naggar; Nisha Gangadharan; Sinéad Heavin; Hugh Kearney; Nicholas J Lench; John Lynch; Mark McCormack; Mary O' Regan; Karl Podesta; Kevin Power; Anthony S Rogers; Charles A Steward; Brian Sweeney; David Webb; Mary Fitzsimons; Marie Greally Journal: Eur J Hum Genet Date: 2020-04-01 Impact factor: 4.246
Authors: Mustafa Tosur; Claudia Soler-Alfonso; Katie M Chan; Michael M Khayat; Shalini N Jhangiani; Qingchang Meng; Ahmad Refaey; Donna Muzny; Richard A Gibbs; David R Murdock; Jennifer E Posey; Ashok Balasubramanyam; Maria J Redondo; Aniko Sabo Journal: Pediatr Diabetes Date: 2021-08-19 Impact factor: 4.866