Deep intronic NIPBL variants underlie unresolved Cornelia de Lange syndrome revealed by integrated epigenomic and transcriptomic analysis.

NIPBL

De novo deep intronic NIPBL variants creating or activating cryptic splice sites, with pseudoexon inclusion, premature termination codons and predicted NMD

About 30% of clinically diagnosed Cornelia de Lange syndrome (CdLS) cases remain without a molecular cause, suggesting non-coding variants. This study investigated 10 patients with classical CdLS who were negative for NIPBL, SMC1A, SMC3, RAD21 and HDAC8: five had a CdLS episignature (blood, saliva or skin) and underwent trio deep sequencing of the entire NIPBL locus plus targeted RNA-seq, while the others had genome sequencing. De novo deep intronic NIPBL variants were found in all five episignature-positive patients, and two further variants in episignature-negative patients, for seven distinct variants in introns 4, 10, 21 and 32. Six were predicted to create or activate a cryptic splice site, and RNA-seq confirmed pseudoexon inclusion in three patients, with premature termination codons and predicted NMD; aberrant transcript expression differed between blood and fibroblasts.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

A clear demonstration of the value of a stepwise approach, episignature, then whole-locus sequencing, then RNA, for unresolved CdLS: these variants are by design missed by exome sequencing. On a genome the target is already captured; the point is to systematically interpret deep intronic NIPBL variation when the phenotype fits, with the episignature serving as functional evidence. The difference in expression between blood and fibroblasts is a reminder that tissue choice matters for RNA studies.

Analysis by Dr Thibaut Benquey