Novel Identification of Genetic Variants in Musculoskeletal Pathways Implicated in Familial Femoroacetabular...

Femoroacetabular impingement (FAI) of the hip results from altered morphology of the proximal femur and/or acetabulum, creating abnormal contact between these structures during normal hip range of motion. The etiology of this structural phenotype is unknown. This study aimed to identify common single-nucleotide variants (SNVs) among two families with seemingly heritable FAI. Additionally, this study examined biologic networks among proteins encoded by identified SNVs and surveyed the literature regarding the role of these proteins in musculoskeletal development. Methodologically, blood samples were collected from affected and unaffected members of two separate families with a pattern of heritable FAI. Exome sequencing identified SNVs, and a protein-protein interaction network assessment, in addition to a literature review, was performed to better understand the role of variant-associated genes in musculoskeletal development. Results showed 33 and 43 variant-associated genes affected in Family 1 and Family 2, respectively. Although no overlap in variant-associated genes was found between families, network analysis showed that variant-associated genes are functionally interconnected and are known to interact with each other. Furthermore, the variant-associated genes are broadly associated with musculoskeletal development. Ultimately, genetic analysis of two families of multiple generations of FAI revealed variations in genes regulating musculoskeletal development, with several being critical local regulators of bone morphogenesis.