Abstract
Cornelia de Lange Syndrome (CdLS) is a well described multiple malformation syndrome caused by alterations in genes encoding subunits or regulators of the cohesin complex. In approximately 70% of CdLS patients, pathogenic NIPBL variants are detected and 15% of them are predicted to affect splicing. Moreover, a large portion of genetic variants in NIPBL was shown to be somatic mosaicism. Here we report two family members with different expression of the CdLS phenotype. In both individuals, a c.869-2A>G (r.869_1495del) substitution was detected, affecting a conserved splice-acceptor site. Deep sequencing revealed the presence of somatic mosaicism in the mother. The substitution was detected in 23% of the sequencing reads using DNA derived from blood samples and 51% in DNA from buccal swabs. The analysis of blood DNA of the son excluded the presence of somatic mosaicism. Correlation of molecular and clinical data revealed that various distribution of genetic alteration in different cell types had an impact on the expression of observed clinical features in both individuals.
Highlights
Cornelia de Lange syndrome (CdLS; OMIM: 1227470, 300590, 610759, 614701, and 300882) is a rare genetic disorder characterized by a highly variable clinical presentation. It is caused by genetic alterations in NIPBL, SMC1A, SMC3, HDAC8, and RAD21 (Krantz et al, 2004; Tonkin et al, 2004; Musio et al, 2006; Deardorff et al, 2007, 2012a,b)
Genetic alterations in NIPBL have been detected in approximately 70% of CdLS patients (OMIM: 608667) (Nizon et al, 2016)
Additional studies have shown that somatic mosaicism is very frequent in CdLS patients
Summary
Cornelia de Lange syndrome (CdLS; OMIM: 1227470, 300590, 610759, 614701, and 300882) is a rare genetic disorder characterized by a highly variable clinical presentation It is caused by genetic alterations in NIPBL, SMC1A, SMC3, HDAC8, and RAD21 (Krantz et al, 2004; Tonkin et al, 2004; Musio et al, 2006; Deardorff et al, 2007, 2012a,b). We report a correlation of clinical and molecular data of two family members with a genetic variant in NIPBL affecting a conserved splice-acceptor site. Both Individuals were previously reported as patients harboring a heterozygous germline mutation (Teresa-Rodrigo et al, 2014). Additional molecular analysis revealed this variant to be somatic mosaicism in the mother, explaining her milder CdLS phenotype in comparison to her son, who is not mosaic for the disease-causing variant
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