The pathogenic variant c.258+533_459+403del in SBDS gene is the commonest rare variant in Italy and shows a founder effect

Shwachman-Diamond syndrome is a rare autosomal recessive disorder (SDS; OMIM #260400) mainly characterized by bone marrow failure, exocrine pancreatic insufficiency, and skeletal defects. The first causative gene is SBDS, identified in 2003, and patients clinically affected by SDS carry mainly SBDS mutations, and most of them are represented by common pathogenic variants derived from genetic conversion events between SBDS and its pseudogene, SBDSP1. The Italian Registry of SDS collected the index cases who received a clinical SDS diagnosis with the demonstration of SBDS biallelic mutations; one of these is always represented by the [c.258+2T>C], while the second one includes either the [c.183_184delinsTA>CT] or [c.183_184delinsTA>CT+c.258+2T>C] or [c.258+2T>C] in, respectively, 59, 12.5 and 10.83% of cases entered until May 2022. In the 17,67% the SBDS genotype is completed by fourteen different types of rare, private, pathogenic variants and all these alleles were observed once among Italian cases, except for [c.187G>T] and [c.258+533_459+403del] alleles, which were observed in two and four unrelated families, respectively. The first one is present in two families, both originating from Northern Tuscany, while for the second allele, the deletion, three families originate from Sicily and one from Lazio. The presence of the deletion in four families (corresponding to 3.31% of index cases), pushed us to investigate if it could be due to a founder effect, with the same mutation originating from a single ancestral event in all cases. Genotyping the region surrounding the SBDS locus, we defined a common haplotype in the families coming from Sicily, while a completely different one resulted in the family originated from Lazio. This result, identifying the most likely ancestral haplotype associated with the deletion of exon 3, suggested a potential founder effect that might be localized in the provinces of Palermo and Messina, in the middle of the North of Sicily. Our result finds a prompt application in routine molecular diagnostics: to know that a causative mutation is a founder mutation it could improve the diagnosis and the genetic counselling in a genetic disease. In addition, providing evidence that in Italy the deletion [c.258+533_459+403del] originated independently twice in two different geographical place (Sicily and Lazio), this study suggests that this deletion could be quite frequent among “rare” SDS mutations and thus with high priority for testing.