Heather Pekeles1, Andrea Accogli2, Nassima Boudrahem-Addour3, Laura Russell4, Fabienne Parente4, Myriam Srour5. 1. Faculty of Medicine, McGill University, Montreal, Canada. 2. Division of Pediatric Neurology, Departments of Pediatrics and Neurology & Neurosurgery, McGill University, Montreal, Canada; Scientific Institute for Research and Healthcare, Istituto Giannina Gaslini, Genova, Italy; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, and Maternal and Children's Sciences, Università degli Studi di Genova, Italy. 3. Child Health and Human Development Program, McGill University Health Center (MUHC) Research Institute, Montreal, Canada. 4. Division of Medical Genetics, Department of Medicine, McGill University, Montreal, Canada. 5. Division of Pediatric Neurology, Departments of Pediatrics and Neurology & Neurosurgery, McGill University, Montreal, Canada. Electronic address: myriam.srour@mcgill.ca.
Abstract
BACKGROUND: Recent technological advances have improved the understanding and identification of the genetic basis of intellectual disability (ID) and global developmental delay (GDD). Next-generation sequencing panels of ID genes are now available for clinical testing; however, their overall yield in clinical practice has not yet been investigated. AIM: We determined the diagnostic yield of ID gene panels in a clinical setting and explored whether any clinical features are associated with an increased diagnostic yield. METHODS: We performed a systematic retrospective chart review of all patients with ID/GDD who underwent an ID gene panel between April 2014 and July 2017 at our institution. Chi-square analysis assessed whether any specific clinical features were significantly associated with a positive diagnostic yield. RESULTS: Forty-eight subjects (18 females, 30 males; median age: 7.5 years) were included. Consanguinity was present in 17%, autism in 38%, seizures in 42%, nonspecific dysmorphic features in 67%, and abnormalities on neurological examination in 56%; furthermore, 29% of the cohort was nonverbal and 4% was nonambulatory. Four different gene panels were used. The diagnostic yield was 21% (10/48) overall, and 38% with the more recent trio-based panel. Eight of 10 patients had de novo pathogenic dominant mutations, one had an inherited pathogenic autosomal dominant mutation, and one had compound heterozygous pathogenic recessive mutations. No clinical feature was significantly associated with an increased diagnostic yield. CONCLUSIONS: Our study suggests that ID gene panels have a high yield and are a valuable diagnostic tool in the evaluation of children with ID/GDD.
BACKGROUND: Recent technological advances have improved the understanding and identification of the genetic basis of intellectual disability (ID) and global developmental delay (GDD). Next-generation sequencing panels of ID genes are now available for clinical testing; however, their overall yield in clinical practice has not yet been investigated. AIM: We determined the diagnostic yield of ID gene panels in a clinical setting and explored whether any clinical features are associated with an increased diagnostic yield. METHODS: We performed a systematic retrospective chart review of all patients with ID/GDD who underwent an ID gene panel between April 2014 and July 2017 at our institution. Chi-square analysis assessed whether any specific clinical features were significantly associated with a positive diagnostic yield. RESULTS: Forty-eight subjects (18 females, 30 males; median age: 7.5 years) were included. Consanguinity was present in 17%, autism in 38%, seizures in 42%, nonspecific dysmorphic features in 67%, and abnormalities on neurological examination in 56%; furthermore, 29% of the cohort was nonverbal and 4% was nonambulatory. Four different gene panels were used. The diagnostic yield was 21% (10/48) overall, and 38% with the more recent trio-based panel. Eight of 10 patients had de novo pathogenic dominant mutations, one had an inherited pathogenic autosomal dominant mutation, and one had compound heterozygous pathogenic recessive mutations. No clinical feature was significantly associated with an increased diagnostic yield. CONCLUSIONS: Our study suggests that ID gene panels have a high yield and are a valuable diagnostic tool in the evaluation of children with ID/GDD.
Authors: Zornitza Stark; Rebecca E Foulger; Eleanor Williams; Bryony A Thompson; Chirag Patel; Sebastian Lunke; Catherine Snow; Ivone U S Leong; Arina Puzriakova; Louise C Daugherty; Sarah Leigh; Christopher Boustred; Olivia Niblock; Antonio Rueda-Martin; Oleg Gerasimenko; Kevin Savage; William Bellamy; Victor San Kho Lin; Roman Valls; Lavinia Gordon; Helen K Brittain; Ellen R A Thomas; Ana Lisa Taylor Tavares; Meriel McEntagart; Susan M White; Tiong Y Tan; Alison Yeung; Lilian Downie; Ivan Macciocca; Elena Savva; Crystle Lee; Ain Roesley; Paul De Fazio; Jane Deller; Zandra C Deans; Sue L Hill; Mark J Caulfield; Kathryn N North; Richard H Scott; Augusto Rendon; Oliver Hofmann; Ellen M McDonagh Journal: Am J Hum Genet Date: 2021-07-29 Impact factor: 11.025
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