Clarification of molecular basis of congenital limb anomalies

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K20862
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0902:General internal medicine and related fields
• Research Institution: Hamamatsu University School of Medicine
• Principal Investigator: YAMOTO Kaori 浜松医科大学, 医学部, 特任研究員 (00906919)
• Project Period (FY): 2021-08-30 – 2023-03-31
• Keywords: 先天性四肢形成不全症 / 全ゲノム解析 / TP63 / PORCN

Outline of Final Research Achievements

Congenital limb anomalies are clinically and genetically heterogeneous. Ｗe reported two patients with PORCN variants identified by re-analyses of whole exome sequencing; 1) a maternally inherited PORCN variant in a Japanese boy with ocular and limb manifestations, and developmental delay and 2) a novel PORCN intronic variant in a mother and her daughter with focal dermal hypoplasia. In addition, we carried out whole genome sequencing in 23 patients from 28 families with congenital limb anomalies in which underlying genetic causes including pathogenic copy-number variants remained undetected in our previous studies. We identified a deep intronic variant in TP63 which is known as a causative gene for split hand and foot malformation.

Free Research Field

遺伝学

Academic Significance and Societal Importance of the Research Achievements

疾患原因が未解明であった症例に対して、全エクソーム解析の再解析および全ゲノム解析を施行し、新たに3家系で疾患原因となる遺伝子変異を同定できた。本研究の成果として、X染色体劣性PORCN non-Goltz spectrumという新たな疾患概念を支持する研究結果は、臨床的意義の高いものである。また、スプライス異常予測ツールを用いることで、これまで病的意義が不明であったintron変異の中から効率的に候補バリアントを絞り込むことが可能であり、今後、遺伝子診断率向上につながる可能性が示された。