Using medical exome sequencing to identify the causes of neurodevelopmental disorders: Experience of 2 clinical units and 216 patients

E Chérot (1) , B Keren (2, 3, 4) , C Dubourg (1, 5) , W Carré (1) , M Fradin (1) , A Lavillaureix (2) , A Afenjar (2, 6) , L Burglen (6) , S Whalen (6) , P Charles (2) , I Marey (2) , S Heide (2) , A Jacquette (2) , D Heron (2) , D Doummar (6) , D Rodriguez (6) , T Billette de Villemeur (6) , M-L Moutard (6) , A Guët (7) , J Xavier (8) , D Périsse (9, 2) , David Cohen (10) , F Demurger (1) , C Quélin (1) , C Depienne (11) , S Odent (5) , C Nava (11) , V David (1, 5) , L Pasquier (1, 12) , C Mignot (2, 13)

1 CHU Pontchaillou [Rennes]
2 CHU Pitié-Salpêtrière [AP-HP]
3 Groupe de Recherche Clinique "Déficience Intellectuelle et Autisme" - Paris
4 GRC ConCer-LD
5 IGDR - Institut de Génétique et Développement de Rennes
6 CHU Trousseau [APHP]
7 Hôpital Louis Mourier - AP-HP [Colombes]
8 ISIR - Institut des Systèmes Intelligents et de Robotique
9 UPMC - Université Pierre et Marie Curie - Paris 6
10 ISIR - Institut des Systèmes Intelligents et Robotique
11 ICM - Institut du Cerveau = Paris Brain Institute
12 CIC - Centre d'Investigation Clinique [Rennes]
13 GRC - Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme

Although whole-exome sequencing (WES) is the gold standard for the diagnosis of neurodevelopmental disorders (NDDs), it remains expensive for some genetic centers. Commercialized panels comprising all OMIM-referenced genes called "medical exome" (ME) constitute an alternative strategy to WES, but its efficiency is poorly known. In this study, we report the experience of 2 clinical genetic centers using ME for diagnosis of NDDs. We recruited 216 consecutive index patients with NDDs in 2 French genetic centers, corresponded to the daily practice of the units and included non-syndromic intellectual disability (NSID, n = 33), syndromic ID (NSID = 122), pediatric neurodegenerative disorders (n = 7) and autism spectrum disorder (ASD, n = 54). We sequenced samples from probands and their parents (when available) with the Illumina TruSight One sequencing kit. We found pathogenic or likely pathogenic variants in 56 index patients, for a global diagnostic yield of 25.9%. The diagnosis yield was higher in patients with ID as the main diagnosis (32%) than in patients with ASD (3.7%). Our results suggest that the use of ME is a valuable strategy for patients with ID when WES cannot be used as a routine diagnosis tool.

Keywords: medical exome; molecular strategy; intellectual disability; autism

Domains: Life Sciences [q-bio]; Genetics; Human genetics; Life Sciences [q-bio]; Neurons and Cognition [q-bio.NC]; Neurobiology

E Chérot, B Keren, C Dubourg, W Carré, M Fradin, et al.. Using medical exome sequencing to identify the causes of neurodevelopmental disorders: Experience of 2 clinical units and 216 patients. Clinical Genetics, 2018, 93 (3), pp.567-576. ⟨10.1111/cge.13102⟩. ⟨hal-01743766⟩