OBJECTIVE: Whole exome sequencing (WES) represents a significant breakthrough in clinical genetics as a powerful tool for etiological discovery in neurodevelopmental disorders. To better characterize the genetic landscape of neurodevelopmental disorders, we analyzed patients in our pediatric neurogenetics clinic who underwent WES. METHODS: We performed a retrospective cohort study on 78 patients with various neurodevelopmental disabilities and unrevealing workup prior to WES. We characterized their molecular diagnoses, clinical features, and whether their previous treatment plan changed due to WES results. RESULTS: The overall presumptive diagnostic rate for our cohort was 41% (n = 32 of 78 patients). Nineteen patients had a single autosomal dominant (AD) disorder, 11 had a single autosomal recessive (AR) disorder, 1 had an X-linked dominant disorder, and 1 had both an AD and an AR disorder. The 32 patients with pathogenic or likely pathogenic variants exhibited various neurobehavioral and neuroimaging abnormalities, including intellectual disability/developmental delay (n = 28), cerebral palsy-like encephalopathy (n = 11), autism spectrum disorder (n = 5), delayed/hypomyelination (n = 7), and cerebellar abnormalities (n = 9). The results of WES affected management for all patients with a presumptive diagnosis, triggering reproductive planning (n = 27), disease monitoring initiation (n = 4), investigation of systemic involvement of the disorder(s) (n = 6), alteration of presumed disease inheritance pattern (n = 7), changing of prognosis (n = 10), medication discontinuation (n = 5) or initiation (n = 2), and clinical trial education (n = 3). INTERPRETATION: The high diagnostic yield of WES supports its use in pediatric neurology practices. It may also lead to earlier diagnosis, impacting medical management, prognostication, and family planning. WES therefore serves as a critical tool for the child neurologist.
OBJECTIVE: Whole exome sequencing (WES) represents a significant breakthrough in clinical genetics as a powerful tool for etiological discovery in neurodevelopmental disorders. To better characterize the genetic landscape of neurodevelopmental disorders, we analyzed patients in our pediatric neurogenetics clinic who underwent WES. METHODS: We performed a retrospective cohort study on 78 patients with various neurodevelopmental disabilities and unrevealing workup prior to WES. We characterized their molecular diagnoses, clinical features, and whether their previous treatment plan changed due to WES results. RESULTS: The overall presumptive diagnostic rate for our cohort was 41% (n = 32 of 78 patients). Nineteen patients had a single autosomal dominant (AD) disorder, 11 had a single autosomal recessive (AR) disorder, 1 had an X-linked dominant disorder, and 1 had both an AD and an AR disorder. The 32 patients with pathogenic or likely pathogenic variants exhibited various neurobehavioral and neuroimaging abnormalities, including intellectual disability/developmental delay (n = 28), cerebral palsy-like encephalopathy (n = 11), autism spectrum disorder (n = 5), delayed/hypomyelination (n = 7), and cerebellar abnormalities (n = 9). The results of WES affected management for all patients with a presumptive diagnosis, triggering reproductive planning (n = 27), disease monitoring initiation (n = 4), investigation of systemic involvement of the disorder(s) (n = 6), alteration of presumed disease inheritance pattern (n = 7), changing of prognosis (n = 10), medication discontinuation (n = 5) or initiation (n = 2), and clinical trial education (n = 3). INTERPRETATION: The high diagnostic yield of WES supports its use in pediatric neurology practices. It may also lead to earlier diagnosis, impacting medical management, prognostication, and family planning. WES therefore serves as a critical tool for the child neurologist.
Authors: Terry Vrijenhoek; Eline M Middelburg; Glen R Monroe; Koen L I van Gassen; Joost W Geenen; Anke M Hövels; Nine V Knoers; Hans Kristian Ploos van Amstel; Gerardus W J Frederix Journal: Eur J Hum Genet Date: 2018-06-29 Impact factor: 4.246
Authors: Laurel K Willig; Josh E Petrikin; Laurie D Smith; Carol J Saunders; Isabelle Thiffault; Neil A Miller; Sarah E Soden; Julie A Cakici; Suzanne M Herd; Greyson Twist; Aaron Noll; Mitchell Creed; Patria M Alba; Shannon L Carpenter; Mark A Clements; Ryan T Fischer; J Allyson Hays; Howard Kilbride; Ryan J McDonough; Jamie L Rosterman; Sarah L Tsai; Lee Zellmer; Emily G Farrow; Stephen F Kingsmore Journal: Lancet Respir Med Date: 2015-04-27 Impact factor: 30.700
Authors: Tiong Yang Tan; Sebastian Lunke; Belinda Chong; Dean Phelan; Miriam Fanjul-Fernandez; Justine E Marum; Vanessa Siva Kumar; Zornitza Stark; Alison Yeung; Natasha J Brown; Chloe Stutterd; Martin B Delatycki; Simon Sadedin; Melissa Martyn; Ilias Goranitis; Natalie Thorne; Clara L Gaff; Susan M White Journal: Eur J Hum Genet Date: 2019-07-18 Impact factor: 4.246
Authors: Carolien G F de Kovel; Steffen Syrbe; Eva H Brilstra; Nienke Verbeek; Bronwyn Kerr; Holly Dubbs; Allan Bayat; Sonal Desai; Sakkubai Naidu; Siddharth Srivastava; Hande Cagaylan; Uluc Yis; Carol Saunders; Martin Rook; Susanna Plugge; Hiltrud Muhle; Zaid Afawi; Karl-Martin Klein; Vijayakumar Jayaraman; Ramakrishnan Rajagopalan; Ethan Goldberg; Eric Marsh; Sudha Kessler; Christina Bergqvist; Laura K Conlin; Bryan L Krok; Isabelle Thiffault; Manuela Pendziwiat; Ingo Helbig; Tilman Polster; Ingo Borggraefe; Johannes R Lemke; Marie-José van den Boogaardt; Rikke S Møller; Bobby P C Koeleman Journal: JAMA Neurol Date: 2017-10-01 Impact factor: 18.302
Authors: Elisa A Mahler; Jessika Johannsen; Konstantinos Tsiakas; Katja Kloth; Sabine Lüttgen; Chris Mühlhausen; Bader Alhaddad; Tobias B Haack; Tim M Strom; Fanny Kortüm; Thomas Meitinger; Ania C Muntau; René Santer; Christian Kubisch; Davor Lessel; Jonas Denecke; Maja Hempel Journal: Dtsch Arztebl Int Date: 2019-03-22 Impact factor: 5.594