Abstract
BackgroundCornelia de Lange syndrome (CdLS), a rare, multisystemic disorder, has been linked to genetic alterations in NIPBL, SMC1A, SMC3, HDAC8, and RAD21 genes. Approximately 60% of CdLS patients harbor various NIPBL variants. Genetic changes predicted to affect NIPBL gene splicing represent 15% of all NIPBL genetic abnormalities. Yet, only a few studies have investigated the molecular consequences of such variants.Case presentationThis study reports two novel, intronic NIPBL genetic variants in unrelated CdLS patients with the characteristic phenotype. A c.6954 + 3A > C substitution and a c.5862 + 1delG deletion were identified, one of each, in a 6 year-old boy and 39 month-old girl. Further studies confirmed that both variants introduce premature termination codons, resulting in the formation of truncated proteins p.(Ser2255LeufsTer20) and p.(Leu1955Ter), respectively.ConclusionSingle nucleotide alterations located within the conserved splice-donor site of intronic regions of the NIPBL gene can give rise to a premature termination of the translation and cause significant changes in the sequence of mRNA transcripts and NIPBL protein structure and function. The latter underline development of Cornelia de Lange syndrome phenotype.
Highlights
Cornelia de Lange syndrome (CdLS), a rare, multisystemic disorder, has been linked to genetic alterations in Nipped-B-like protein (NIPBL), SMC1A, SMC3, HDAC8, and RAD21 genes
Cornelia de Lange Syndrome (CdLS; OMIM# 1227470, 300,590, 610,759, 614,701, and 300,882) is a rare, multisystemic disorder characterized by the facial dysmorphism, limb malformations, intellectual disability, and developmental delay [1,2,3,4,5,6]
Genetic alterations of NIPBL, SMC1A, SMC3, HDAC8, and RAD21 genes are believed to trigger the development of Cornelia de Lange syndrome
Summary
Single nucleotide alterations located within the conserved splice-donor site of intronic regions of the NIPBL gene can give rise to a premature termination of the translation and cause significant changes in the sequence of mRNA transcripts and NIPBL protein structure and function.
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