The study to elucidate the background of molecular genetics that cause holoprosencephaly spectrum disorders the diversity of phenotype

• Project/Area Number: 19K17320
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Tohoku University
• Principal Investigator: ABE Yu 東北大学, 医学系研究科, 非常勤講師 (00789787)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2020: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 全前脳胞症 / holoprosencephaly / Binder症候群 / HPE / Holoprosencephaly / Binderoid cleft lip / Binder 症候群 / SHH

Outline of Research at the Start

2019年度は対象症例の収集に当てる。対象は年齢・性別を問わず、臨床症状として口唇顎口蓋裂・眼窩間距離の狭小化など、顔面正中部の低形成による顔貌異常を伴う症例とする。2020年度は収集した症例について、全前脳胞症スペクトラムのdriver mutation / modifier variantを同定し、Binder症候群、Binderoid cleft lip/plateを含む、HPE スペクトラムの広がりを分子遺伝学的に明らかにするための解析に当てる。

Outline of Final Research Achievements

A Targeted NGS panel was performed in 5 HPE cases and 3 Binderoid complete cleft lip / plate cases. Among them, a de novo reported frameshift variant was identified on the causative gene SIX3 in a HPE case. In 2 cases of HPE, the variants with unclear pathological significance were found, but it was difficult to narrow down the candidate variants. The remaining two HPEs are still being analyzed. A missense mutation in KAT6A was identified in a Binderoid complete cleft plate suspected case and diagnosed as Arboleda-Tham syndrome.

Academic Significance and Societal Importance of the Research Achievements

現在日本国内において全前脳胞症 (HPE)、Binder 症候群、および Binderoid complete cleft lip/plate について遺伝子解析を実施する体制は整っていない。本研究では典型的なHPE 症例において既知の原因遺伝子である SIX3 が同定され、本研究での解析方法により速やかにHPE の遺伝学的診断が可能であることが示された。現在、 さらに残りの17 症例の解析を継続中である。本研究の結果は、これらの疾患における遺伝子型と表現型、環境要因の関連、およびHPE スペクトラムの広がりを分子遺伝学的に明らかにする足がかりとなるものである。

Research Products

• [Journal Article] The effect of dietary protein restriction in a case of molybdenum cofactor deficiency with MOCS1 mutation (2021)
  • Author(s): Yu Abe, Yu Aihara, Wakaba Endo, Hiroshi Hasegawa, Kimiyoshi Ichida, Mitsugu Uematsu, Shigeo Kure
  • Journal Title: Mol Genet Metab Rep Volume: 26 Pages: 100716-100716
  • DOI: 10.1016/j.ymgmr.2021.100716
  • Peer Reviewed / Open Access
• [Presentation] The effect of dietary protein restriction in a case of molybdenum cofactor deficiency with MOCS1 mutation (2021)
  • Author(s): Yu Abe, Yu Aihara, Wakaba Endo, Hiroshi Hasegawa, Kimiyoshi Ichida, Mitsugu Uematsu, Shigeo Kure
  • Organizer: The 22nd Annual Meeting of The Infantile Seizure Society (ISS) and International Symposium on Genetic Role of Neurometabolic Diseases with Infantile Epilepsy (ISGNIE)
  • Int'l Joint Research