A study of molecular genetic analysis to hereditary conjugated hyperbilirubinemia with next-generation sequencing

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K10148
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Nagoya City University
• Principal Investigator: Takao Togawa 名古屋市立大学, 医薬学総合研究院(医学), 助教 (10792814)
• Co-Investigator(Kenkyū-buntansha): 齋藤 伸治 名古屋市立大学, 医薬学総合研究院(医学), 教授 (00281824) ; 杉浦 時雄 名古屋市立大学, 医薬学総合研究院(医学), 研究員 (10381881)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 遺伝性抱合型高ビリルビン血症 / Dubin-Johnson症候群 / Rotor症候群 / 新生児胆汁うっ滞 / 遺伝学的解析 / 体質性黄疸

Outline of Final Research Achievements

We aimed to establish a method of molecular genetic diagnoses to hereditary conjugated hyperbilirubinemia, neonatal Dubin-Johnson syndrome (nDJS) and Rotor syndrome (RS). Another target was to clarify genotype-phenotype correlations in these syndromes.
We designed a method of targeted next-generation sequencing with 61 candidate genes including ABCC2, and OATP1B1 and OATP1B3, and those are responsible genes for nDJS and RS, respectively. During this study period, we analyzed 124 patients with neonatal/infantile intrahepatic cholestasis and identified 40 (32.3%) patients as having a molecular genetic diagnosis. Because a diagnostic ratio was 25.7% in our previous study using a 18 genes panel, we improved the diagnostic ratio to those patients. Nine of 40 patients (22.5%) having a definitive molecular diagnosis were nDJS. Consequently, we reported its unique clinical features, pathological liver findings, and pathogenic variants of ABCC2 in the Journal of pediatrics.

Free Research Field

新生児学

Academic Significance and Societal Importance of the Research Achievements

新生児Dubin-Johnson症候群やRotor症候群はかつて非常に稀な疾患とされ，その疾患の詳細は不明であった．近年，次世代高速シークエンサーの登場により，このような稀な遺伝性疾患を分子レベルで診断できるようになった．
今回の研究により，日本人，東アジア人に於いて，遺伝子診断できる新生児Dubin-Johnson症候群患者は比較的高い頻度で見られることが分かった．そして，新生児，乳児期に特徴的な症状経過をたどること，肝臓病理学所見は成人のものと異なることが証明された．一方Rotor症候群は発見されず，極めて稀な疾患であることが再認識された．