Exome-Sequencing, with Prior Linkage Analysis, Identifies a Candidate Gene Causing
Maturity-Onset Diabetes of the Young (MODY) in Thais Family
Ninareeman Binnima1,* , Watip Tangjittipokin1, Kanchana Chanprasert1, Jatuporn
Sujjitjoon1, Prapaporn Jungtrakoon1, Pa-thai Yenchitsomanus2, Nattachet Plengvidhya3,#
1
Department of Immunology and Immunology Graduate Program, Faculty of Medicine
Siriraj Hospital, Mahidol University, Thailand
2
Division of Molecular Medicine, Department of Research and Development, Faculty of
Medicine Siriraj Hospital, Mahidol University, Thailand
3
Division of Endocrinology and Metabolism, Faculty of Medicine Siriraj Hospital, Mahidol
University, Thailand
*en_nina@hotmail.com, #sinpv.natpl@gmail.com
Abstract
Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes. It is
characterized by an early onset (usually before age 25 years), non-insulin dependence and
autosomal dominant inheritance. Genetic factors play crucial roles in development of
MODY. Recently, MODY is caused by mutation in at least thirteen different genes including
HNF-4α, GCK, HNF-1α, IPF-1, HNF-1β, NeuroD1, KLF11, CEL, PAX4, INS, BLK, ABCC8
and KCNJ11. However, MODY with unknown genetic etiology, or MODY-X, is still
common in many ethnic groups. Because 80% of Thai MODY are MODY-X, this study
aimed to identify novel MODY genes by linkage analysis and exome-sequencing. Linkage
analysis was done in 27 members from a Thai MODY-X family. LOD score ≥ 2.5 was
identified in chromosome 9, 11 and 22. Exome-sequencing was executed in two affected and
two unaffected family members. Two novel variants, PTCH1 p.M1071L and GGT5 p.A48T,
located in these high LOD regions were selected. Four in silico programs including PolyPhen
V2.0.23, SIFT, Mutation Taster and VarioWatch were used to predict the possible deleterious
effect of these certain variants on protein functions. Only PTCH1 p.M1071L has deleterious
effects. This variant was validated by Sanger sequencing and genotyped in family members.
PTCH1 p.M1071L was partially segregated with diabetes in this family. This variant was not
detected in 200 non-diabetic controls and other 66 MODY-X probands. Interestingly, PTCH1
is expressed in pancreatic islets and involved in islets development and function. Therefore,
PTCH1 may be a pathogenic gene causing MODY in this family. Thus, linkage analysis
combined with exome-sequencing is a new strategy to identify novel MODY genes
Acknowledgements: This work was supported by Siriraj Graduate Thesis Scholarship,
Siriraj Grant for Research and Development, Mahidol University Grant and Thailand
Research Fund.
Keywords: maturity-onset diabetes of the young, linkage analysis, exome-sequencing,
MODY, diabetes