Fortuitous detection of a submicroscopic deletion at 1q25 in a girl with Cornelia‐de Lange syndrome carrying t(5;13)(p13.1;q12.1) by array‐based comparative genomic hybridization

Abstract

We report on a 2-year-old Japanese girl with Cornelia-de Lange syndrome (CdLS) who had mental and growth retardation, together with characteristic facial anomalies and mild extremity malformations. She had a balanced chromosomal translocation, 46,XX,t(5;13)(p13.1;q12.1) de novo. Surprisingly, this was the same translocation that had provided a clue to the identification of a major causative gene for CdLS, NIPBL [Krantz et al., 2004; Tonkin et al., 2004]. Using fluorescence in situ hybridization (FISH), the breakpoint was confirmed to lie within NIPBL at 5p13.1. Furthermore, array-based comparative genomic hybridization (array-CGH) demonstrated a cryptic 1-Mb deletion harboring six known genes at 1q25-q31.1. A FISH analysis of her parents confirmed that the deletion was de novo. Although patients with interstitial deletions at 1q are rare, some of their features were similar to those observed in our patient, indicating that her clinical manifestations are likely to be affected by not only the disruption of NIPBL but also the concomitant microdeletion at 1q25-q31.1. The present case suggests that array-CGH can uncover cryptic genomic aberrations affecting atypical phenotypes even in well-known congenital disorders.

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

“…In conclusion, this study represents the first systematic array‐CGH analyses of patients with CdLS‐like features, previously screened for mutations in the two major causative genes. It expands the studies by Borck et al (10), Schoumans et al (18) and Hayashi et al (17) altogether reporting on 4 of 19 patients found by array‐CGH to carry genomic imbalances.…”

“…Till now only a few studies have applied array‐CGH to a restricted number of CdLS patients. These studies have identified de novo rearrangements including a submicroscopic deletion of terminal chromosome 1q (10), a serendipitous additional submicroscopic deletion at 1q25‐q31.1 in a girl with the causative (i.e., NIPBL targeting) t(5;13)(p13.1;q12.1) translocation (17) and a 9p24.3 (telomeric) duplication of 0.6 Mb (18). To investigate chromosomal rearrangements pointing to additional positional candidate CdLS genes, we analyzed by array‐CGH a subgroup of 24 CdLS patients negative for NIPBL and SMC1L1 mutations.…”

Breakpoint Mapping and Array CGH in Translocations: Comparison of a Phenotypically Normal and an Abnormal Cohort

“…Furthermore, these observations have important implications for the establishment of genotypephenotype correlations because they imply that the contribution of novel unbalanced regions independent of the breakpoints needs to be considered. For example, Hayashi et al 30 described a 1 Mb de novo deletion at 1q25 in a girl with Cornelia de Lange syndrome [MIM 122470] and a t(5;13)(p13.1;q12.1), and it appeared that both the deletion and the disruption of the NIPBL [MIM 608677] gene by the 5p translocation breakpoint contributed to the phenotype.…”

Genomic imbalances in patients with a clinical presentation in the spectrum of Cornelia de Lange syndrome

“…The genomic technology of array Comparative Genomic Hybridisation (aCGH), which monitors losses or gains in chromosome regions that may harbour novel candidate genes, is not yet a standard test for investigation of NIPBL - and SMC1A -mutation-negative CdLS patients [11,18,34,35], but results obtained with the technique to date are consistent with those of > 30 conventional cytogenetic and FISH-targeted studies that have shown chromosomal abnormalities associated with the CdLS phenotype involving almost all of the chromosomes (reviewed [36]). One study has used aCGH to study probands with CdLS-like features, who had been previously screened for mutations in the two major causative genes; however, this was performed in a relatively small patient cohort [35].…”