MODY 5 and 6 have been shown to be low-penetrant MODYs. As the genetic background of unknown MODY is assumed to be similar, a new analytical strategy is applied here to elucidate genetic predispositions to unknown MODY. We examined to find whether there are major MODY gene loci remaining to be identified using SNP linkage analysis in Japanese. Whole-exome sequencing was performed with seven families with typical MODY. Candidates for novel MODY genes were examined combined with in silico network analysis. Some peaks were found only in either parametric or non-parametric analysis; however, none of these peaks showed a LOD score greater than 3.7, which is approved to be the significance threshold of evidence for linkage. Exome sequencing revealed that three mutated genes were common among 3 families and 42 mutated genes were common in two families. Only one of these genes, MYO5A, having rare amino acid mutations p.R849Q and p.V1601G, was involved in the biological network of known MODY genes through the intermediary of the INS. Although only one promising candidate gene, MYO5A, was identified, no novel, high penetrant MODY genes might remain to be found in Japanese MODY.
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The authors are very grateful to the patients and their families for their participation in the study. We thank K Yokoyama, J Kawada, and H Tsuchida for technical assistance.
YH, KH, ST, SS, II, and JT contributed to the study design. YH, KH, ME, HI, and YS performed the genetic experiments and analyzed and interpreted the genetic data. YH, KH, and JT wrote the manuscript. All coauthors read and approved the manuscript.
This work was supported by a Health and Labor Science Research Grant for Research on Rare and Intractable Diseases from the Japanese Ministry of Health, Labor and Welfare, a Grant-in-Aid for Scientific Research from the Japanese Ministry of Science, Education, Sports, Culture and Technology, and a Strategic International Research Cooperative Program Grant from Japan Science and Technology Agency.
Conflict of interest
The authors declare that they have no conflict of interest.
Electronic supplementary material
Supplementary Fig. S2 LOD scores of linkage analysis of 32 individuals from seven MODY families with typical modalities of MODY(TIF 28683 kb)
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Horikawa, Y., Hosomichi, K., Enya, M. et al. No novel, high penetrant gene might remain to be found in Japanese patients with unknown MODY. J Hum Genet 63, 821–829 (2018). https://doi.org/10.1038/s10038-018-0449-4