Permanent neonatal diabetes in siblings with novel C109Y INS mutation transmitted by an unaffected parent with somatic mosaicism.

Mutations involving the insulin (INS) gene are a common cause of permanent neonatal diabetes (PND). Although INS mutations typically occur de novo and germline INS mutations transmitted to offspring by unaffected parents has been described, somatic mosaicism in a parent with an INS mutation has not been previously reported. We describe two siblings (one brother and one sister) with PND (26- and 19-yr old diagnosed at 3 and 7 months old, respectively), whose parents were unaffected. We performed genetic analysis of leukocyte DNA for this family. Both patients were found to carry the novel heterozygous c.326G>A substitution in exon 3 of INS, resulting in a p.C109Y change of the insulin protein. Analyses of leukocyte DNA from the parents revealed low level mutation in the sequencing trace of the father, raising the possibility of somatic mosaicism. Real-time polymerase chain reaction (PCR) analysis showed he had approximately 73% of the mutant allele relative to his affected son. This first report of somatic mosaicism in an unaffected parent with an INS mutation suggests that parental mosaicism may be responsible for the transmission of PND in patients with de novo INS mutations. As such, appropriate counseling for recurrent risks should be considered and we recommend that molecular genetic testing for future siblings at birth should be offered to the parents of children with INS mutation.