Abstract
BackgroundCornelia de Lange syndrome (CdLS) is a rare autosomal-dominant disorder characterised by facial dysmorphism, growth and psychomotor developmental delay and skeletal defects. To date, causative mutations in the NIPBL (cohesin regulator) and SMC1A (cohesin structural subunit) genes account for > 50% and 6% of cases, respectively.MethodsWe recruited 50 patients with a CdLS clinical diagnosis or with features that overlap with CdLS, who were negative for mutations at NIPBL and SMC1A at molecular screening. Chromosomal rearrangements accounting for the clinical diagnosis were screened for using array Comparative Genomic Hybridisation (aCGH).ResultsFour patients were shown to carry imbalances considered to be candidates for having pathogenic roles in their clinical phenotypes: patient 1 had a 4.2 Mb de novo deletion at chromosome 20q11.2-q12; patient 2 had a 4.8 Mb deletion at chromosome 1p36.23-36.22; patient 3 carried an unbalanced translocation, t(7;17), with a 14 Mb duplication of chromosome 17q24.2-25.3 and a 769 Kb deletion at chromosome 7p22.3; patient 4 had an 880 Kb duplication of chromosome 19p13.3, for which his mother, who had a mild phenotype, was also shown to be a mosaic.ConclusionsNotwithstanding the variability in size and gene content of the rearrangements comprising the four different imbalances, they all map to regions containing genes encoding factors involved in cell cycle progression or genome stability. These functional similarities, also exhibited by the known CdLS genes, may explain the phenotypic overlap between the patients included in this study and CdLS. Our findings point to the complexity of the clinical diagnosis of CdLS and confirm the existence of phenocopies, caused by imbalances affecting multiple genomic regions, comprising 8% of patients included in this study, who did not have mutations at NIPBL and SMC1A. Our results suggests that analysis by aCGH should be recommended for CdLS spectrum cases with an unexplained clinical phenotype and included in the flow chart for diagnosis of cases with a clinical evaluation in the CdLS spectrum.
Highlights
Cornelia de Lange syndrome (CdLS) is a rare autosomal-dominant disorder characterised by facial dysmorphism, growth and psychomotor developmental delay and skeletal defects
The 50 probands negative for NIPBL and SMC1A mutations were considered an ideal cohort to scan for the presence of genomic gains/losses by array Comparative Genomic Hybridisation (aCGH), in the search for novel genes responsible for phenotypes with features that overlap CdLS
We identified four probands with large or de novo copy number variants (CNVs) (Table 1), whose clinical data at birth and at age of evaluation are summarised in Table 2
Summary
Cornelia de Lange syndrome (CdLS) is a rare autosomal-dominant disorder characterised by facial dysmorphism, growth and psychomotor developmental delay and skeletal defects. Causative mutations in the NIPBL (cohesin regulator) and SMC1A (cohesin structural subunit) genes account for > 50% and 6% of cases, respectively. Cornelia de Lange syndrome (CdLS) is a rare, genetically heterogeneous (OMIM #122470, #300590 and #610759), multiple congenital anomaly/intellectual disability disease [1,2], characterised by distinctive facial dysmorphism, pre- and post-natal growth deficiency, psychomotor delay, Known CdLS-associated genes encode structural and regulatory proteins of the cohesin pathway, which is involved in chromosome segregation, DNA repair, gene expression and chromosome conformation [8]. Locus heterogeneity in CdLS has been demonstrated by the X-linked form caused by mutation of the SMC1A gene, which encodes a subunit of the cohesin complex [28]. The remaining CdLS cases may be due to as yet undetected mutations in the known genes or by other causative anomalies
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