Whole-Exome Sequencing Analysis Identifies Risk Genes in Atlantoaxial Dislocation Patients with Sandwich Fusion

Area of Science:

• Genetics
• Orthopedics
• Developmental Biology

Background:

• Klippel-Feil syndrome (KFS) is a rare congenital disorder characterized by cervical vertebral fusion.
• Atlantoaxial dislocation (AAD) in KFS presents diagnostic and treatment challenges.
• The genetic underpinnings of KFS sandwich fusion remain largely unknown due to its rarity.

Purpose of the Study:

• To investigate the genetic basis of Klippel-Feil syndrome with sandwich fusion.
• To identify potential pathogenic genes contributing to this rare congenital disorder.
• To explore genotype-phenotype correlations, particularly regarding disease severity.

Main Methods:

• Whole-exome sequencing (WES) was performed on 68 unrelated Chinese patients with KFS sandwich fusion.
• Genetic data was compared against a control group of 219 individuals without musculoskeletal disorders.
• Analyses included mutational burden assessments to pinpoint candidate genes.

Main Results:

• Significant genetic variations were identified in patients with KFS sandwich fusion.
• Genes such as KMT5A, HYDIN, and PCDHB4 emerged as potential contributors.
• Oligogenic effects were observed in severe cases, with MEOX1 mutations linked to spinal issue severity.

Conclusions:

• The study provides critical insights into the genetic architecture of KFS sandwich fusion.
• Identified genes offer a foundation for understanding the disorder's pathogenesis.
• Findings pave the way for future research and potential therapeutic strategies.