Chromosome 13q14.2-q14.3 and 15q26.2-qter deletions detected by array-CGH in two patients with Cornelia de Lange syndrome

Cornelia de Lange syndrome (CdLS) is a rare, dominantly inherited, multisystem disorder characterized by peculiar facial dysmorphisms, upper limb abnormalities, growth and cognitive retardation. Mutations in NIPBL and SMC1L1 genes, encoding a regulatory and a subunit of the cohesin complex respectively, account for up to 55% of the CdLS patients. Further genetic heterogeneity, suggested by the high percentage of mutation negative patients, is attested by the recent involvement of a third gene (SMC3) found mutated in a CdLS patient. In addition several chromosomal rearrangements have been reported in CdLS-like patients raising the issue of clinical heterogeneity of CdLS. Array based comparative genomic hybridisation (array-CGH) may be an helpful tool to 1) evaluate novel loci that might harbor additional CdLS genes and 2) define clinical entities overlapping with CdLS due to chromosomal abnormalities. Nineteen patients fitting the clinical CdLS diagnosis but negative to NIPBL and SMC1L1 mutations were tested by a full coverage array-CGH. Two carriers of copy number losses at two distinct genomic regions were detected: in both cases deletions were de novo and were shown by microsatellite analysis to affect the paternal chromosome. A female patient presenting with severe growth restriction, typical facial dysmorphisms, heart defects, gastroesophageal reflux and moderate MR, showed a 15q26.2-qter deletion, sized ~8 Mb of a gene poor region. Among the included 28 genes, IGF1R, which haploinsufficiency has been associated with pre and post-natal growth retardation, a common sign of CdLS, is of relevance to the phenotype. A male patient, displaying classical facial dysmorphisms, hirsutism, growth (<3%) and psychomotor delay, epilepsy, had an interstitial 13q14.2-q14.3. deletion, sized 1 Mb and encompassing 8 genes. Recently this region has been reported to include genes with a polymorphic not imprinted monoallelic expression from either the maternal or paternal copy. However in silico analysis of the mapped genes did not reveal potential candidates. Patients such as those here described represent a resource to disclose distinct genetic alterations in cases with phenotypic similarities.