STRUCTURAL VARIATION IN SBDS GENE, WITH LOSS OF EXON 3, IN TWO NEW SHWACHMAN-DIAMOND PATIENTS

International Guidelines of Shwachman-Diamond Syndrome suggest that detection of bi-allelic pathogenic variants in SBDS gene, localized at 7q11.21, can confirm the clinical diagnosis of this rare disease [Dror et al. 2011]. Targeted mutation analysis of exon 2 by PCR_RFLP discloses in at least 90% of SDS patients one of the three common mutations, (c.185_184TA>CT, c.258+2T>C and the combination of c.[183_184TA>CT:258+2T>C] on one allele). Two of the common mutations are observed concomitantly in approximately 62% of SDS patients [Myers et al. 2014]. We recently found two families, each of them with two affected children, carrying only the [c.258+2T>C] mutation, in whom no other mutation was found after complete sequencing analysis of all five exons and their flanking intronic regions of SBDS. Western-blot analysis using SBDS antibody didn’t demonstrate any SBDS protein in these patients, suggesting the presence of a more complex anomaly on the second allele. A similar family was reported by Costa et al. in 2007. They, in fact, described the only case reported thus far of a paternally inherited large deletion removing exon 3, and derived from an excision event mediated by AluSx elements which are present in introns 2 and 3. Using a similar method, we were able to identify in both families a full deletion of exon 3: the coordinates of the deleted region in GRCh37/hg19 assembly are chr7: g.66457801-66458666, with a deletion size of 866 bp. According to nomenclature for sequence variations (den Dunnen and Antonarakis, 2000), we described the mutations [c.258+533_459+403del]. It overlaps, but not completely, with the one reported by Costa et al. (2007). The two families we studied are unrelated, the family names of the two parents carrying the deletion of exon 3 are uncommon in Italy and originate from different Italian areas as Sicily and Lazio.