AUTHOR=Liu Yuzhao , Fan Xuesong , Qian Kun , Wu Changshun , Zhang Laibo , Yuan Lin , Man Zhentao , Wu Shuai , Li Ping , Wang Xianquan , Li Wei , Zhang Yuanqing , Sun Shui , Yu Chenxi TITLE=Deciphering the pathogenic role of rare RAF1 heterozygous missense mutation in the late-presenting DDH JOURNAL=Frontiers in Genetics VOLUME=15 YEAR=2024 URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2024.1375736 DOI=10.3389/fgene.2024.1375736 ISSN=1664-8021 ABSTRACT=Background

Developmental Dysplasia of the Hip (DDH) is a skeletal disorder where late-presenting forms often escape early diagnosis, leading to limb and pain in adults. The genetic basis of DDH is not fully understood despite known genetic predispositions.

Methods

We employed Whole Genome Sequencing (WGS) to explore the genetic factors in late-presenting DDH in two unrelated families, supported by phenotypic analyses and in vitro validation.

Results

In both cases, a novel de novo heterozygous missense mutation in RAF1 (c.193A>G [p.Lys65Glu]) was identified. This mutation impacted RAF1 protein structure and function, altering downstream signaling in the Ras/ERK pathway, as demonstrated by bioinformatics, molecular dynamics simulations, and in vitro validations.

Conclusion

This study contributes to our understanding of the genetic factors involved in DDH by identifying a novel mutation in RAF1. The identification of the RAF1 mutation suggests a possible involvement of the Ras/ERK pathway in the pathogenesis of late-presenting DDH, indicating its potential role in skeletal development.