De Novo Mutations Causing Shwachman-Diamond Syndrome and a Founder Mutation in SBDS in the French Canadian Population

We summarize the molecular findings in a patient cohort with Shwachman-Diamond syndrome that underwent genetic diagnostic testing. We could confirm a molecular diagnosis in 81 individuals. Our data is consistent with previous findings that the most common mutations in SBDS are recurrent gene conversion mutations in exon 2, c.258+2T>C or c.183_184delinsCT. The patients diagnosed either had two recurrent mutations (78%), or one recurrent mutation and a rare family-specific mutation (22%). We identified six unrelated individuals with SDS of French Canadian decent with the c.120del (p.Arg39fsX) mutation. Molecular analysis revealed that this mutation occurs with a founder haplotype. The opposing SBDS mutation present in these individuals was the common c.258+2T>C mutation, which was on a different haplotype in all five families. In addition, we estimated that approximately 9% (5 out of a subset of 54 patients with parent information) of the SDS individuals had a de novo mutation on one allele and an inherited mutation on the other allele. The de novo mutations were either recurrent gene conversion mutations (n=3) or rare point mutations (n=2). The occurrence of de novo mutation requires that parental carrier testing be performed for accurate familial risk assessment.