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Submitted on December 19, 2006
Accepted on February 15, 2007
Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, UK; Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK; Department of Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK
* To whom correspondence should be addressed. E-mail: sian.ellard{at}rdeft.nhs.uk.
Context: Activating mutations in the KCNJ11 gene, which encodes the Kir6.2 subunit of the pancreatic beta-cell KATP channel, result in permanent and transient neonatal diabetes. The majority of KCNJ11 mutations are spontaneous, but the parental origin of these mutations is not known.
Objective: To determine the parental origin of de novo KCNJ11 mutations and investigate the possibility of mosaicism in transmitting parents.
Design: We identified 68 index cases with a KCNJ11 mutation where neither parent was known to be affected. DNA was available from both parents of 41 probands. The parental origin of the mutation was determined in 18 families by examination of pedigrees, microsatellite analysis or allele specific PCR.
Results: A non-significant excess of paternally derived mutations was found with 13/18 (72%) shown to have arisen on the paternal allele. There was no evidence to suggest an association with increased age at conception. In two families there were half-siblings with permanent neonatal diabetes born to an unaffected father, suggesting germline mosaicism that was confirmed by the presence of the R201C mutation in one father's semen. Somatic mosaicism was detected in one unaffected mother and this mutation will also be present in her germ cells.
Conclusion: De novo KCNJ11 mutations can arise either during gametogenesis or embryogenesis. The possibility of germline mosaicism means that future siblings are at increased risk of neonatal diabetes and we recommend that molecular genetic testing is routinely offered at birth for subsequent siblings of children with de novo KCNJ11 mutations.
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