Whole-exome sequencing and high throughput genotyping identified KCNJ11 as the thirteenth MODY gene.
BACKGROUND
Maturity-onset of the young (MODY) is a clinically heterogeneous form of diabetes characterized by an autosomal-dominant mode of inheritance, an onset before the age of 25 years, and a primary defect in the pancreatic beta-cell function. Approximately 30% of MODY families remain genetically unexplained (MODY-X). Here, we aimed to use whole-exome sequencing (WES) in a four-generation MODY-X family to identify a new susceptibility gene for MODY.


METHODS
WES (Agilent-SureSelect capture/Illumina-GAIIx sequencing) was performed in three affected and one non-affected relatives in the MODY-X family. We then performed a high-throughput multiplex genotyping (Illumina-GoldenGate assay) of the putative causal mutations in the whole family and in 406 controls. A linkage analysis was also carried out.


RESULTS
By focusing on variants of interest (i.e. gains of stop codon, frameshift, non-synonymous and splice-site variants not reported in dbSNP130) present in the three affected relatives and not present in the control, we found 69 mutations. However, as WES was not uniform between samples, a total of 324 mutations had to be assessed in the whole family and in controls. Only one mutation (p.Glu227Lys in KCNJ11) co-segregated with diabetes in the family (with a LOD-score of 3.68). No KCNJ11 mutation was found in 25 other MODY-X unrelated subjects.


CONCLUSIONS
Beyond neonatal diabetes mellitus (NDM), KCNJ11 is also a MODY gene ('MODY13'), confirming the wide spectrum of diabetes related phenotypes due to mutations in NDM genes (i.e. KCNJ11, ABCC8 and INS). Therefore, the molecular diagnosis of MODY should include KCNJ11 as affected carriers can be ideally treated with oral sulfonylureas.
CNRS-UMR8199, Lille Pasteur Institute, Lille, France.
Amélie
A
Bonnefond
Julien
J
Philippe
Emmanuelle
E
Durand
Aurélie
A
Dechaume
Marlène
M
Huyvaert
Louise
L
Montagne
Michel
M
Marre
Beverley
B
Balkau
Isabelle
I
Fajardy
Anne
A
Vambergue
Vincent
V
Vatin
Jérôme
J
Delplanque
David
D
Le Guilcher
Franck
F
De Graeve
Cécile
C
Lecoeur
Olivier
O
Sand
Martine
M
Vaxillaire
Philippe
P
Froguel
D001483:Base Sequence; D002874:Chromosome Mapping; D004252:DNA Mutational Analysis; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D005602:France; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008126:Lod Score; D008969:Molecular Sequence Data; D010375:Pedigree; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D000099161:Kcnj11 Channel
D024661:Potassium Channels, Inwardly Rectifying; D000099161:Kcnj11 Channel