Identification of De Novo Chromosomal Translocations Disrupting NIPBL in a Patient With Cornelia de Lange Syndrome by Full Genome Analysis

Abstract

ABSTRACT Background Cornelia de Lange syndrome (CdLS) is a rare genetic disorder characterized by congenital multiple anomalies, developmental delay, and distinctive facial features. Methods We performed chromosomal microarray analysis (CMA), whole exome sequencing (WES), linked‐read whole‐genome sequencing (WGS) and optical genome mapping (OGM) to investigate an undiagnosed case of CdLS. Results A male patient presented clinical features consistent with CdLS, including a short nose, synophrys, small hands, hearing impairment, refractory complex partial seizures, and developmental delay. Amniocentesis at 28 gestational weeks and karyotyping revealed a presumably balanced translocation between chromosome 5 and chromosome 6. CMA and WES failed to identify copy number variants or a molecular diagnosis. Further analysis using WGS and OGM identified two translocation events on chromosome 5, resulting in three derivative chromosomes: 46,XY, der(2)t(2;5)(q32.3;p13.2),der(5)t(5;6)(p13.1;q12),der(6)t(2;6)(q32.3;q12)ins(6;5)(q12;p13.1p13.2). These rearrangements disrupted the NIPBL gene, a key gene with CdLS, splitting it across derivative chromosomes 2 and 6. Phasing studies revealed that these translocations originated from the paternal lineage. Conclusions This case highlights the intricate genetic underpinnings of CdLS in this patient and underscores the diagnostic value of high‐resolution genomic analyses in elucidating complex chromosomal rearrangements.

Keywords

• Cornelia de Lange syndrome (CdLS)
• cytogenomics
• linked‐read whole‐genome sequencing (WGS)
• optical genome mapping (OGM)
• translocation