Deep intronic NIPBL de novo mutations and differential diagnoses revealed by whole genome and RNA sequencing in Cornelia de Lange syndrome patients

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...

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Bibliographic Details
Published in:Human mutation 2022-12, Vol.43 (12), p.1882-1897
Main 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
Format: Article
Language:eng ; fre
Subjects:
Cell Cycle Proteins - genetics
clustered mutations
Cornelia de Lange syndrome
De Lange Syndrome - diagnosis
De Lange Syndrome - genetics
De Lange Syndrome - pathology
De Lange's syndrome
Developmental disabilities
Diagnosis, Differential
Differential diagnosis
Genomes
Humans
Introns
kataegis
Life Sciences
Mutation
neurodevelopmental disorder
NIPBL
noncoding sequence
Phenotype
Ribonucleic acid
RNA
Saliva
Sequence Analysis, RNA
Whole genome sequencing
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Summary: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. 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.
ISSN:1059-7794
1098-1004
DOI:10.1002/humu.24438