Pathological variants in genes associated with disorders of sex development and central causes of hypogonadism in a whole-genome reference panel of 8380 Japanese individuals

Naomi Shiga; Yumi Yamaguchi-Kabata; Saori Igeta; Jun Yasuda; Shu Tadaka; Takamichi Minato; Zen Watanabe; Junko Kanno; Gen Tamiya; Nobuo Fuse; Kengo Kinoshita; Shigeo Kure; Akiko Kondo; Masahito Tachibana; Masayuki Yamamoto; Nobuo Yaegashi; Junichi Sugawara

doi:10.1038/s41439-022-00213-w

Pathological variants in genes associated with disorders of sex development and central causes of hypogonadism in a whole-genome reference panel of 8380 Japanese individuals

Hum Genome Var. 2022 Sep 28;9(1):34. doi: 10.1038/s41439-022-00213-w.

Authors

Naomi Shiga¹, Yumi Yamaguchi-Kabata^{1

2}, Saori Igeta¹, Jun Yasuda^{1

2

3}, Shu Tadaka^{1

2}, Takamichi Minato¹, Zen Watanabe¹, Junko Kanno¹, Gen Tamiya^{1

2

4}, Nobuo Fuse^{1

2}, Kengo Kinoshita^{2

5

6

7}, Shigeo Kure^{1

2}, Akiko Kondo¹, Masahito Tachibana¹, Masayuki Yamamoto^{1

2

7}, Nobuo Yaegashi^{1

2}, Junichi Sugawara^{8

9}

Affiliations

¹ Graduate School of Medicine, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan.
² Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, 980-8573, Japan.
³ Miyagi Cancer Center Research Institute, 47-1, Nodayama, Medeshima-Shiode, Natori, 981-1293, Japan.
⁴ Statistical Genetics Team, RIKEN Center for Advanced intelligence Project, Nihonbashi 1-chome Mitui Building, 15th Floor, 1-4-1 Nihonbashi, Chuo-ku, Tokyo, 103-0027, Japan.
⁵ Graduate School of Information Sciences, Tohoku University, 6-3-09, Aza-aoba, Armaki, Aoba-ku, Sendai, 980-8579, Japan.
⁶ Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan.
⁷ Advanced Research Center for Innovations in Next-Generation Medicine, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8573, Japan.
⁸ Graduate School of Medicine, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan. jsugawara@med.tohoku.ac.jp.
⁹ Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, 980-8573, Japan. jsugawara@med.tohoku.ac.jp.

Abstract

Disorders of sex development (DSD) comprises a congenital condition in which chromosomal, gonadal, or anatomical sex development is atypical. In this study, we screened for pathogenic variants in 32 genes associated with DSDs and central causes of hypogonadism (CHG) in a whole-genome reference panel including 8380 Japanese individuals constructed by Tohoku Medical Megabank Organization. Candidate pathogenic (P) or likely pathogenic (LP) variants were extracted from the ClinVar, InterVar, and Human Gene Mutation databases. Ninety-one candidate pathological variants were found in 25 genes; 28 novel candidate variants were identified. Nearly 1 in 40 (either ClinVar or InterVar P or LP) to 157 (both ClinVar and InterVar P or LP) individuals were found to be carriers of recessive DSD and CHG alleles. In these data, genes implicated in gonadal dysfunction did not show loss-of-function variants, with a relatively high tendency of intolerance for haploinsufficiency based on pLI and Episcore, both of which can be used for estimating haploinsufficiency. We report the types and frequencies of causative variants for DSD and CHG in the general Japanese population. This study furthers our understanding of the genetic causes and helps to refine genetic counseling of DSD and CHG.

Abstract

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