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Permanent Neonatal Diabetes due to Paternal Germline Mosaicism for an Activating Mutation of the KCNJ11 Gene Encoding the Kir6.2 Subunit of the ß-Cell Potassium Adenosine Triphosphate Channel

Diabetes and Vascular Medicine (A.L.G., E.L.E., L.W.H., A.T.H., S.E.), Peninsula Medical School, Exeter EX2 5AX, United Kingdom; Department of Pediatrics (E.A.C., R.S.), Dalhousie University and IWK Health Centre, Halifax B3K 6R8, Canada; Department of Pediatrics (T.C.), Ste. Justine Hospital, Universite de Montreal, Montreal H3T 1C5, Canada; and Wessex Clinical Genetics Service and Division of Human Genetics (I.K.T.), Southampton University and Hospitals National Health Service Trust, Southampton SO16 5YA, United Kingdom

Address all correspondence and requests for reprints to: Dr. Sian Ellard, Molecular Genetics, Old Pathology Building, Royal Devon & Exeter Hospital, Barrack Road, Exeter EX2 5DW, United Kingdom. E-mail: s.ellard{at}exeter.ac.uk.

Activating mutations in the KCNJ11 gene encoding for the Kir6.2 subunit of the ß-cell ATP-sensitive potassium channel have recently been shown to be a common cause of permanent neonatal diabetes. In 80% of probands, these are isolated cases resulting from de novo mutations. We describe a family in which two affected paternal half-siblings were found to be heterozygous for the previously reported R201C mutation. Direct sequencing of leukocyte DNA showed that their clinically unaffected mothers and father were genotypically normal. Quantitative real-time PCR analysis of the father’s leukocyte DNA detected no trace of mutant DNA. These results are consistent with the father being a mosaic for the mutation, which is restricted to his germline. This is the first report of germline mosaicism in any form of monogenic diabetes. The high percentage of permanent neonatal diabetes cases due to de novo KCNJ11 mutations suggests that germline mosaicism may be common. The possibility of germline mosaicism should be considered when counseling recurrence risks for the parents of a child with an apparently de novo KCNJ11 activating mutation.

This work was supported in Exeter by grants from Wellcome Trust, Diabetes UK. A.T.H. is a Wellcome Trust Research Leave Clinical Fellow.

Abbreviations: Ct, Crossing point; K_ATP, ATP-sensitive potassium; PNDM, permanent neonatal diabetes; SDS, SD score; SUR1, sulfonylurea receptor subunit.

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