Intragenic and large NIPBL rearrangements revealed by MLPA in Cornelia de Lange patients

Abstract

Cornelia de Lange syndrome (CdLS) is a rare multisystemic congenital anomaly disorder that is characterised by intellectual disability and growth retardation, congenital heart defects, intestinal anomalies, facial dysmorphism (including synophyris and high arched eyebrows) and limb reduction defects. Mutations in three cohesin-associated genes encoding a key regulator (NIPBL, chr 5p13.2) and one structural component of the cohesin ring (SMC1A, chr Xp11) occur in about 65% of CdLS patients. NIPBL is the major causative gene, and accounts for 40-60% of CdLS patients as shown by a number of mutational screening studies that indicate a wide mutational repertoire of mainly small deletions and point mutations. Only a few data are available concerning the occurrence of large NIPBL rearrangements or intragenic deletions or duplications involving whole exons. We used multiplex ligation-dependent probe amplification (MLPA) to study 132 CdLS patients negative to the standard mutation NIPBL test out of a cohort of 200 CdLS patients. A total of 7 out of 132 patients were found to carry NIPBL alterations, including two large gene deletions extending beyond the gene, four intragenic multi-or single-exon deletions and one singleexon duplication. These findings show that MLPA leads to a 5.3% increase in the detection of mutations when used in addition to the standard NIPBL scan, and contributes per se to the molecular diagnosis of 3.5% (7/200) of clinically diagnosed CdLS patients. It is recommended that MLPA be included in the CdLS diagnostic flow chart.

Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism

“…Large-scale structural genomic rearrangements that disrupt the function of known CdLS genes have been reported as affecting NIPBL ,13 14 SMC1A ,15 HDAC8 12 and RAD21. 8 Rare copy number variants (CNVs) involving 1p36.23–36.22, 7p22.3, 17q24.2–25.3, 19p13.3 and 20q11.2-q12 have also been reported in association with CdLS-like features 16…”

Global transcriptional disturbances underlie Cornelia de Lange syndrome and related phenotypes

“…Up to 60% of CdLS cases harbor mutations in NIPBL, which encodes a regulatory protein loading the cohesin complex onto the sister chromatids. Copy number variants (CNVs) in the NIPBL locus are found in approximately 5% of NIPBL point mutation-negative CdLS cases, while mosaic mutations in NIPBL are reported to account for an additional 23% (7)(8)(9)(10). SMC1A and SMC3 are core structural components of the cohesin complex.…”

Spectrum of NIPBL gene mutations in Polish patients with Cornelia de Lange syndrome

“…In fact, a de novo balanced translocation involving chromosome 5 facilitated identification of the NIPBL gene (Tonkin et al 2004). Recently, a few reports have been published presenting several cases with sub-microscopic deletions encompassing the NIPBL gene, with the size of aberration ranging from 4.2 kb (a single exon) to 2 Mb deletion, including not only the NIPBL gene but also 14 adjacent genes (Bhuiyan et al 2007; Ratajska et al 2010; Oliver et al 2010, Murray et al 2012; Pehlivan et al 2012; Russo et al 2012). The incidence of genomic aberrations was estimated to be 4–5 % of CdLS patients negative for the NIPBL point mutation (Pehlivan et al 2012; Russo et al 2012).…”

“…Moreover, in a few cases, a large genomic rearrangement involving the NIPBL gene has been detected, indicating even higher complexity of the genetic background of the syndrome. Observed genomic alterations were mostly deletions, encompassing one or more of NIPBL exons; however, also, a few pathogenic duplications were reported (Bhuiyan et al 2007; Ratajska et al 2010; Oliver et al 2010; Murray et al 2012; Pehlivan et al 2012, Russo et al 2012). …”