# Deciphering the pathogenic role of rare RAF1 heterozygous missense mutation in the late-presenting DDH

## TL;DR

This study identifies a rare RAF1 mutation linked to late-presenting hip dysplasia, suggesting its role in skeletal development and disease.

## Contribution

A novel de novo RAF1 mutation is linked to late-presenting DDH, implicating the Ras/ERK pathway in its pathogenesis.

## Key findings

- A de novo RAF1 mutation (c.193A>G [p.Lys65Glu]) was found in two unrelated late-presenting DDH cases.
- The mutation altered RAF1 structure and function, affecting the Ras/ERK signaling pathway.
- In vitro and computational validations confirmed the mutation's impact on downstream signaling.

## Abstract

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.

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.

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.

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.