We used an unbiased genome-wide approach to identify exonic variants segregating with diabetes in a multigenerational Finnish family. At least eight members of this family presented with diabetes with age of diagnosis ranging from 18 to 51 years and a pattern suggesting autosomal dominant inheritance. We sequenced the exomes of four affected members of this family and performed follow-up genotyping of additional affected and unaffected family members. We uncovered a novel nonsynonymous variant (p.Trp314Arg) in the Wolfram syndrome 1 (WFS1) gene that segregates completely with the diabetic phenotype. Multipoint parametric linkage analysis with 13 members of this family identified a single linkage signal with maximum logarithm of odds score 3.01 at 4p16.2-p16.1, corresponding to a region harboring the WFS1 locus. Functional studies demonstrate a role for this variant in endoplasmic reticulum stress, which is consistent with the β-cell failure phenotype seen in mutation carriers. This represents the first compelling report of a mutation in WFS1 associated with dominantly inherited nonsyndromic adult-onset diabetes.
Considerable advances have been made in our understanding of the genetics of monogenic diabetes, which accounts for 1–3% of diabetes cases (1–3). The identification of causative genetic variants responsible for monogenic diabetes has revealed critical elements of the pathways involved in insulin and glucose metabolism, and in some instances has led to important therapeutic interventions (4). But the list of ∼20 known causative loci for monogenic diabetes is far from complete, as DNA sequencing of known genes has failed to identify mutations in some families (1). The overlap of genes identified in genome-wide association studies and/or candidate gene studies of the more common type 2 diabetes with those of the known monogenic diabetes genes suggests that common genetic pathways may be involved (4). Thus, identifying the as-yet-undefined genes involved in monogenic diabetes would also offer new insights into the genetics of type 2 diabetes.
We set out to identify the genetic cause of diabetes in a four-generation family with an apparent autosomal dominant form of adult-onset diabetes (Fig. 1). Previous sequencing of the exons of known maturity-onset diabetes of the young (MODY) genes in a subset of the affected members of this family failed to identify candidate variants segregating with diabetes. Thus, we sequenced the exomes of four affected members of this family, with follow-up screening of additional affected and unaffected family members, and uncovered a novel nonsynonymous variant in the Wolfram syndrome 1 (WFS1) gene as the likely causative mutation for diabetes in this family.