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

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.