Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism

Background Cornelia de Lange syndrome(CdLS) is a multisystem disorder with distinctive facial appearance, intellectual disability and growth failure as prominent features. Most individuals with typical CdLS have de novo heterozygous loss-of-function mutations in NIPBLwith mosaicindividuals representing a significant proportion. Mutations in other cohesincomponents, SMC1A, SMC3 , HDAC8and RAD21 cause less typical CdLS. Methods We screened 163 affected individuals for coding region mutations in the known genes, 90 for genomic rearrangements, 19 for deep intronic variants in NIPBLand 5 had whole- exome sequencing. Results Pathogenic mutations \[including mosaicchanges] were identified in: NIPBL46 [3\] (28.2%); SMC1A5 \[1\] (3.1%); SMC3 5 \[1\] (3.1%); HDAC86 \[0\] (3.6%) and RAD21 1 \[0\] (0.6%). One individual had a de novo 1.3 Mb deletion of 1p36.3. Another had a 520 kb duplication of 12q13.13 encompassing ESPL1, encoding separase, an enzyme that cleaves the cohesinring. Three de novo mutationswere identified in ANKRD11 demonstrating a phenotypic overlap with KBG syndrome. To estimate the number of undetected mosaiccases we used recursive partitioningto identify discriminating features in the NIPBL- positive subgroup. Filtering of the mutation-negative group on these features classified at least 18% as ‘ NIPBL- like’. A computer composition of the average face of this NIPBL-like subgroup was also more typical in appearance than that of all others in the mutation-negative group supporting the existence of undetected mosaiccases. Conclusions Future diagnostic testing in ‘mutation-negative’ CdLS thus merits deeper sequencing of multiple DNA samples derived from different tissues.