Search for genomic imbalances in a cohort of 24 Cornelia de Lange patients negative for mutations in the NIPBL and SMC1L1 genes

Abstract

Cornelia de Lange syndrome (CdLS) is a rare, multiple congenital anomaly/mental retardation syndrome characterized by varied clinical signs including facial dysmorphism, pre- and post-natal growth defects, small hands and malformations of the upper limbs. Established genetic causes include mutations in the NIPBL (50-60%), SMC1L1 and SMC3 (5%) genes. To detect chromosomal rearrangements pointing to novel positional candidate CdLS genes, we used array-CGH to analyze a subgroup of 24 CdLS patients negative for mutations in the NIPBL and SMC1L1 genes. We identified three carriers of DNA copy number alterations, including a de novo 15q26.2-qter 8-Mb deletion, and two inherited 13q14.2-q14.3 1-Mb deletion and 13q21.32-q21.33 1.5-Mb duplication, not reported among copy number variants. The clinical presentation of all three patients matched the diagnostic criteria for CdLS, and the phenotype of the patient with the 15qter deletion is compared to that of both CdLS and 15qter microdeletion patients.

Premature chromatid separation is not a useful diagnostic marker for Cornelia de Lange syndrome

“…Fifteen of the 16 negative patients were tested for SMC1L1 and underwent array CGH; eight of these have so far been found negative in both analyses, and one previously reported case carries a causative imbalance (Gervasini et al 2008).…”

“…The CdLS cohort consisted of 29 patients, 10 of whom have been described previously (Selicorni et al 2007;Gervasini et al 2008), 14 females and 15 males aged 3-43 years whose clinical diagnosis was made or confirmed by an experienced clinician (A.S.).…”

“…The array CGH analysis of the CdLS patients was done as previously described (Gervasini et al 2008). …”

“…Mutations in two other genes, SMC1L1 and SMC3, are respectively responsible for an Xlinked (OMIM #300590) and another autosomal form of CdLS (OMIM #610759) (Musio et al 2006;Deardorff et al 2007), and their protein products are two structural maintenance of chromosomes (SMC) subunits of the cohesion complex; these mutations account for up to 5% of all CdLS cases (Deardorff et al 2007). Further studies of chromosomal rearrangements in CdLS patients have since indicated additional candidate genes (Gervasini et al 2008), but the molecular basis of the syndrome is still unknown in about 40% of cases.…”

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

“…In patients with a CdLS-like clinical diagnosis who are negative to NIPBL scan, a-CGH has mainly revealed de novo imbalances in various genomic regions that maybe too large to identify new CdLS genes. [8][9][10] Given the length of the NIPBL gene and the plausible failure of its splicing mechanism, MLPA undoubtedly seems to be the most promising additional means of optimising the diagnostic mutation rate. However, only three MLPA-detected CdLS patients have so far been described in the literature, one of which was fortuitously found in the context of a study aimed at evaluating the increased DNA damage sensitivity of CdLS syndrome cell lines.…”