Origin of de novo KCNJ11 mutations and risk of neonatal diabetes for subsequent siblings.
BACKGROUND
Activating mutations in the KCNJ11 gene, which encodes the Kir6.2 subunit of the pancreatic beta-cell K(ATP) 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
Our objective was to determine the parental origin of de novo KCNJ11 mutations and investigate the possibility of mosaicism in transmitting parents.


METHODS
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 nonsignificant excess of paternally derived mutations was found with 13 of 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.


CONCLUSIONS
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.
Edghill
Emma L
EL
Department of Molecular Genetics, Royal Devon and Exeter National Health Service Foundation Trust, Barrack Road, Exeter, United Kingdom.
Gloyn
Anna L
AL
Goriely
Anne
A
Harries
Lorna W
LW
Flanagan
Sarah E
SE
Rankin
Julia
J
Hattersley
Andrew T
AT
Ellard
Sian
S
D000328:Adult; D000483:Alleles; D004247:DNA / Q000235:genetics; D017931:DNA Primers; D003920:Diabetes Mellitus / Q000453:epidemiology* / Q000235:genetics*; D005260:Female; D018095:Germ-Line Mutation / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D018895:Microsatellite Repeats; D009030:Mosaicism; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D015183:Restriction Mapping; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012306:Risk; D000099161:Kcnj11 Channel
D004247:DNA; D017931:DNA Primers; D024661:Potassium Channels, Inwardly Rectifying; D000099161:Kcnj11 Channel