Backround: Type 1 diabetes (T1D) is a complex autoimmune disease with a
strong familial segregation. On the other hand, the recent and rapid increase
in incidence is a proof of the importance of environmental factor in the
etiology of disease. Linkage and Genome-wide association studies had
revealed almost 60 loci associated with the risk of T1D, explaining about 80%
of the total heritability, mostly due to HLA locus. However, many familial T1D
cases remains unexplained.
Objective: To identify rare variants contributing to T1D susceptibility, we
studied a Sardinian family with 9 individuals affected across 3 generations.
Methods: We performed exome sequencing in 3 affected members and a
healthy individual. In addition, all samples were extensively genotyped using
Illumina OmniExpress beadchips for about 750K SNPs. A combined linkage
analysis was carried out.
Results: This combined approach identified three variants predicted to be
damaging that are very rare in the general population (frequency <1%) and
that are likely causing the disease
