Regulatory element deletion cause a down-regulation of ZDHHC15 gene in a proband with Smith Magenis syndrome phenotype

Here, we describe a boy aged 3 years who showed mild facial minor anomalies such as brachycephaly, square face, thick eyebrows, broad palate, generalized hypotonia, developmental delay, behavioural problems (self injury), sleep disorders and congenital heart defect. Based on suspected Smith Magenis syndrome (SMS), chromosomal analysis was performed and showed a 46,XY karyotype. FISH analysis of the SMS locus at 17p11.2, as well as MLPA, mutational analyses and quantitative expression of the RAI1 gene, gave normal results. High-resolution array-CGH analysis disclosed two rare maternal deletions at 4q35.2 and Xq13.3, both yet unreported in healthy subjects according to the Database of Genomic Variants. Whereas it is not possible to assign a pathogenetic role to the 4q35.2 deletion, the Xq13.3 loss of 54 kb involves a predicted conserved insulator that maps 29 kb far from the 5’ end of the ZDHHC15 gene. ZDHHC15 acts as a palmitoyl-transferase in brain, and its null expression has been reported in a syndromic patient. We thus investigated in the patient’s blood the causative role of the identified CNV on ZDHHC15 by RT-qPCR. The ZDHHC15 expression level was significantly reduced in the male proband compared to controls, whereas the expression level in the mother was within the control range.Our results suggest the involvement of ZDHHC15 perturbation in the onset of the proband’s phenotype and point to this gene, sharing interactors with RAI1, as a novel candidate gene for SMS.