RAI1 intragenic deletion and concomitant overexpression in a syndromic patient: Smith-Magenis or Potocki-Lupski syndrome?

Smith-Magenis Syndrome (SMS) [MIM:182290] is a genomic disorder caused by RAI1 gene haploinsufficiency and characterized by intellectual disability, craniofacial dysmorphisms, behavioral and sleep disturbances, speech and motor delay. Here we describe a 17 years old girl with a clinical suspicion of SMS. Upon previous exclusion of 17p11.2 SMS locus deletion, RAI1 mutational screening identified the yet unreported heterozygous variant p.A1091D predicted as likely benign and inherited from the healthy mother. Moreover, MLPA analysis revealed a de novo heterozygous deletion encompassing RAI1 exon 5, that encodes PHD functional domain, consistent with the initial clinical suspicion.In order to verify that the de novo deletion results in RAI1 haploinsufficiency, RT-qPCR studies were carried out but showed an unexpected significant increase in blood transcript levels of both patient and mother compared to those of 10 controls. Moreover, a specific allelic dosage analysis revealed that the deleted allele is overexpressed in the patient and concerns the inherited maternal allele. This result confirms SMS diagnosis, as an overexpression of an aberrant transcript lacking the functional domain was detected.Our finding supports the hypothesis that RAI1 overexpression, shared with the mother, can be mediated by a cis element. Promoter and regulatory regions are under study aiming at identifying variants that could be related with RAI1 overexpression finding. Despite RAI1 overexpression causes Potocki-Lupski Syndrome (PTLS) [MIM:610883], the mother does not resemble a PTLS clinical phenotype. This might be explained by the PTLS high phenotype variability or by penetrance defect as previously reported in other familiar cases.