The study about pathological variants in genes associated with disorders of sex development in a whole-genome reference panel of 8380 Japanese individuals

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K18626
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56040:Obstetrics and gynecology-related
• Research Institution: Tohoku University
• Principal Investigator: Kondo Akiko 東北大学, 医学系研究科, 大学院非常勤講師 (20644818)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: 性分化疾患 / DSD / 性分化関連遺伝子 / 塩基配列変異 / バリアント / 東北メディカル・メガバンク計画 / 全ゲノム解析 / 住民ゲノム参照パネル

Outline of Final Research Achievements

Disorders of sex development (DSD) are congenital disorders in which chromosomal, gonadal, and anatomical sexual development is atypical. In this study, we conducted a screen for pathogenic variants in 32 genes associated with recessive DSD and central causes of hypogonadism (CHG) in a whole genome reference panel established by Tohoku Medical Megabank Organization including 8380 Japanese individuals. Pathogenic candidate (P) or likely pathogenic (LP) variants were annotated with the ClinVar, InterVar, and Human Gene Mutation databases. 91 candidate pathogenic variants were found in 25 genes, and 28 novel candidate variants were identified. Almost 1 in 40 individuals (ClinVar or InterVar P or LP) to 157individuals (both ClinVar and InterVar P or LP) were found to be carriers of recessive DSD and CHG alleles. In this study, we describe the types and frequencies of causative variants of recessive DSD and CHG in the general Japanese population.

Free Research Field

生殖内分泌

Academic Significance and Societal Importance of the Research Achievements

本研究は、東北メディカル・メガバンク機構が構築した日本人8380人の全ゲノム参照パネルにおいて、潜性遺伝形式をとる性分化疾患、中枢性性腺機能低下症およびアンドロゲン受容体遺伝子に関連する遺伝子から抽出した32遺伝子の病的バリアントについて検討した。病的バリアント候補を抽出し、既存の遺伝子バリアントのデータベースを用いて病的妥当性を評価した。25の遺伝子で91の病的バリアント候補を認め、28の新規病的バリアント候補が同定された。本研究は日本人の潜性遺伝形式性分化疾患および中枢性性腺機能低下症の原因解明に役立つことが期待される。