Deep intronic NIPBL de novo mutations and differential diagnoses revealed by whole genome and RNA sequencing in Cornelia de Lange syndrome patients. Issue 12 (23rd July 2022)

• Record Type: Journal Article
• Authors: Coursimault, Juliette; Cassinari, Kévin; Lecoquierre, François; Quenez, Olivier; Coutant, Sophie; Derambure, Céline; Vezain, Myriam; Drouot, Nathalie; Vera, Gabriella; Schaefer, Elise; Philippe, Anaïs; Doray, Bérénice; Lambert, Laëtitia; Ghoumid, Jamal; Smol, Thomas; Rama, Mélanie; Legendre, Marine; Lacombe, Didier; Fergelot, Patricia; Olaso, Robert; Boland, Anne; Deleuze, Jean‐François; Goldenberg, Alice; Saugier‐Veber, Pascale; Nicolas, Gaël
• Is Part Of: Human mutation. Volume 43:Issue 12(2022)
• Page Start: 1882
• Page End: 1897
• Publication Date: 2022-07-23
• Subjects: clustered mutations -- Cornelia de Lange syndrome -- kataegis -- neurodevelopmental disorder -- NIPBL -- noncoding sequence -- whole genome sequencing; Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.24438
• Languages: English
• ISSNs: 1059-7794

Abstract

Abstract: Cornelia de Lange syndrome (CdLS; MIM# 122470) is a rare developmental disorder. Pathogenic variants in 5 genes explain approximately 50% cases, leaving the other 50% unsolved. We performed whole genome sequencing (WGS) ± RNA sequencing (RNA‐seq) in 5 unsolved trios fulfilling the following criteria: (i) clinical diagnosis of classic CdLS, (ii) negative gene panel sequencing from blood and saliva‐isolated DNA, (iii) unaffected parents' DNA samples available and (iv) proband's blood‐isolated RNA available. A pathogenic de novo mutation (DNM) was observed in a CdLS differential diagnosis gene in 3/5 patients, namely POU3F3, SPEN, and TAF1 . In the other two, we identified two distinct deep intronic DNM in NIPBL predicted to create a novel splice site. RT‐PCRs and RNA‐Seq showed aberrant transcripts leading to the creation of a novel frameshift exon. Our findings suggest the relevance of WGS in unsolved suspected CdLS cases and that deep intronic variants may account for a proportion of them. Abstract : Whole genome sequencing and RNA sequencing performed in 5 classical Cornelia de Lange syndrome patients, revealing deep intronic NIPBL de novo mutations and differential diagnoses.