A microdeletion proximal of the critical deletion region is associated with mild Wolf-Hirschhorn syndrome

It is generally accepted that the facial phenotype of WolfHirschhorn syndrome is caused by deletions of either WolfHirschhorn critical regions 1 or 2 (WHSCR 12). Here, we identify a 432?kb deletion located 600?kb proximal to both WHSCR12 in a patient with a WHS facial phenotype. Seven genes are underlying this deletion region including FAM193a, ADD1, NOP14, GRK4, MFSD10, SH3BP2, TNIP2. The clinical diagnosis of WHS facial phenotype was confirmed by 3D facial analysis using dense surface modeling. Our results suggest that the WHSCR12 flanking sequence contributes directly or indirectly to the severity of WHS. Sequencing the WolfHirschhorn syndrome candidate 1 and 2 genes did not reveal any mutations. Long range position effects of the deletion that could influence gene expression within the WHSCR were excluded in EBV cell lines derived from patient lymphoblasts. We hypothesize that either (1) this locus harbors regulatory sequences which affect gene expression in the WHSCR12 in a defined temporal and spatial developmental window or (2) that this locus is additive to deletions of WHSCR12 increasing the phenotypic expression. (c) 2012 Wiley Periodicals, Inc.