Submicroscopic genomic alterations detected by array CGH analysis in a cohort of patients with Silver Russell syndrome found negative to classical genetic and epigenetic tests

Silver Russell syndrome is characterized by pre- and postnatal growth retardation, variable facial dysmorphisms, clinodactyly of the fifth fingers, and sometimes asymmetry of face, trunk and extremities. Genetic and epigenetic aberrations on chromosomes 7 and 11 are commonly found in SRS, leaving out however, a fraction of up to 50% of cases with unknown genetic aetiology. A cohort of 32 clinically selected SRS patients, without detected genetic or epigenetic alterations was analyzed by high resolution array CGH analysis to identify possibly pathogenetic CNVs. Twenty-eight patients (87.5%) were found to carry one or more rare CNVs, according to the Database of Genomic Variants and, overall, 55 rare CNVs, 25 gains (45.5%) and 30 losses (54.5%) were identified. Inheritance, established for 36 of the identified rare CNVs, showed that 7 occurred de novo (19.5%). Interrogation of public databases allowed us to pinpoint genomic regions containing genes, either imprinted or not, that according to their function, appeared plausible candidates for SRS. Interestingly 4 CNVs span genomic regions already associated with growth defects, 3 CNVs contain known genes found altered in previously described SRS patients and 3 CNVs include genes implicated in growth control pathways not yet associated with SRS. These results confirm the genetic heterogeneity of SRS and the high percentage of potentially causative imbalances, attesting the wide clinical expressivity of patients with a phenotype strongly suggestive for this syndrome. Genome-wide scan is reconfirmed an appropriate and powerful tool to achieve a differential diagnosis between SRS and SRS-like patients.