MBD5 molecular screening on Smith Magenis-like Syndrome patients without the typical 17p11.2 deletion

Smith Magenis Syndrome (SMS) is a complex heterogeneous disorder, caused by RAI1 haploinsufficiency and triggered by 17p11.2 deletion or RAI1 gene mutation. Only 50% of patients with a clinical suspicion of SMS bear the known defects, making its diagnosis challenging and suggesting that other loci may underlie SMS-like phenotypes. Notably 2q23.1 deletion and brachydactyly mental retardation (BDMR) syndromes, caused by MBD5 and HDAC4 haploinsufficiency respectively, are two SMS phenotypical and molecular overlapping syndromes as the affected patients seem to show a reduced RAI1 transcript levels, implying that MBD5/HDAC4 regulate RAI1. Here we describe a cohort of 30 SMS-like patients without 17p11.2 deletion, and RAI1 microdeletion or mutation. Array-CGH analysis revealed a 29 kb deletion at 2q23.1 encompassing exons 1 and 2 of MBD5 in one patient, while MBD5 mutational screening identified in a second case an heterozygous missense mutation likely pathogenetic, p.A857T. Unexpectedly the deletion was found in a mosaic condition in the healthy father of the first patient, while the missense mutation, previously described in a child with mental retardation, was maternally inherited. The subsequent RTqPCR showed a MBD5 transcript downregulation in the patient with 2q23.1 deletion, normal RAI1 transcript levels in all the patients and unexpectedly in the SMS-like patient with MBD5 haploinsufficiency too. Our findings corroborate the hypothesis that other loci can be causative of SMS-like phenotypes and for this reason we are setting up a flow chart aiming at improve the molecular diagnosis in SMS-like patients and shed light on pathogenetic mechanisms.