Mutation spectrum of NIPBL gene in Korean patients with Cornelia de Lange syndrome

Abstract

Cornelia de Lange Syndrome (CdLS, also called Brachmann de Lange Syndrome; OMIM 122470) is characterized by multiple malformations, severe growth, mental retardation, and distinctive facial features. Patients with CdLS show clinically variable phenotypes that range from mild to severe. The prevalence of CdLS is estimated to be about 1 in 10,000 ~ 30,000. Although CdLS is inherited as an autosomal dominant or X-linked manner, most cases appear to be sporadic. Currently, heterozygous mutations in the cohesin regulator NIPBL, or the cohesin structural components SMC1A (formerly SMC1L1) and SMC3 have been identified as a cause of CdLS. NIPBL gene mutation has been identified in approximately 20 to 50% of CdLS cases, and 5% of patients show mutations in the SMC1A gene. In this study, the mutation spectrum of NIPBL and SMC1A genes in 13 Korean patients with CdLS was investigated. Five patients (38%) showed mutations in NIPBL and one patient (9%) carried a mutation in SMC1A from the 13 unrelated Korean patients with CdLS. There were 5 novel heterozygous mutations including c.2108C>A (p.Pro703Gln), c.6425G>T (p.Arg2142Ile), c.6530T>C (p.Leu2177Ser), c.6679-6682delGTCA, c.7549delG identified in NIPBL and 1 novel heterozygous mutation, c.2327T>C (p.Val776Ala), in SMC1A. The rest of the 7 CdLS patients who showed negative results in mutation analysis for the NIPBL and SMC1A genes were screened by 4X180K array-based comparative genomic hybridization (array-CGH) to detect common chromosomal rearrangements that may suggest novel candidate CdLS genes. Only two patients showed DNA copy number alterations, including a deletion on chromosome 5q12.1 and a duplication on chromosome 16p11.2. The results of this study suggest the genetic heterogeneity of CdLS. Further analysis will be needed to identify novel candidate gene(s) responsible for CdLS.