Analysis of genes related to cleft lip and palate by next-generation sequencing.

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K10124
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 57060:Surgical dentistry-related
• Research Institution: Tokyo Dental College
• Principal Investigator: Watanabe Akira 東京歯科大学, 歯学部, 教授 (50408324)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: 口唇裂・口蓋裂 / 遺伝子異常 / 次世代シークエンサー

Outline of Final Research Achievements

We used next-generation sequencing approach for a trio analysis of Japanese patients with CL/P and CP, along with their parents. The specific targeted genes included IRF6 (1q32.2), WNT5A (3p14.3), WNT9B (17q21.32), TP63 (3q28), MSX1 (4p16), TFAP2A (6p24.3), PAX9 (14q12-q 13), DLX3 (17q21.33), DLX4 (17q21.33), and MN1 (22q12.1). We discovered a noteworthy missense mutation, 359C>T (P120L), in the DLX4 gene in a single patient with CL/P. Furthermore, novel variants (WNT5A 639+918C>T, TFAP2A 45+2755C>G, WNT9B 904+3061A>G, TP63 1349+8281T>C, PAX9 4+272G>A) in highly conserved sequences within the non-coding regions were observed in three patients with CL/P and two patients with CP. Our genetic analysis of Japanese patients with CL/P, using the next-generation sequencing technology unveiled novel mutations and variants that had eluded previous GWAS. Nonetheless, the underlying causes of CL/P onset remain enigmatic, presenting a continuing challenge in the field of craniofacial genetics.

Free Research Field

口腔外科

Academic Significance and Societal Importance of the Research Achievements

本プロジェクトで口唇裂・口蓋裂の発症原因の追究は前進したものの未だ明らかになっていないのが現状である。今後の展望としてDNAのメチル化，ヒストンのメチル化，ヒストンのアセチル化などの epgenome 異常などの今まで捉えられていない構造異常に興味がわく。ロングリードシークエンサーでDNAメチル化解析に移行し，DNAの配列だけではなくDNAのメチル化で多因子遺伝子疾患の発症メカニズムを解明していけないか？そして、遠い未来ではあるが口唇裂・口蓋裂の治療が、患者に負担のかかる手術だけでなく新たな治療を選択できる医療へと進むだろう。