Whole Genome Sequencing of Patients with Severe Glenoid Dysplasia Identifies HOXA9 as a Candidate Genetic Variant- SOMOS 2024

galvin j, johnson c, say f, free k, eichinger j, patterson b, nepola j, hogue j, dalgard c, colburn z

Abstract accepted at The Society of Military Orthopedic Surgeons 2024 Annual Meeting

Glenoid dysplasia is a rare pathology characterized by failure of development of the posterior glenoid, resulting in severe deformity and alteration of shoulder mechanics. It is largely asymptomatic until approximately 25 to 45 years of age. When patients develop pain, they typically already have severe posterior cartilage wear and early-onset osteoarthritis. Therefore, early detection of glenoid dysplasia may offer an opportunity to intervene in adolescence or counsel patients on their condition so they can modify their activities. The purpose of this study was to identify genetic variants associated with the diagnosis of severe glenoid dysplasia.

Three male patients (mean age: 40.3 yrs, range: 38-43) with severe glenoid dysplasia who underwent blood draw at the time of operative treatment were analyzed. High molecular weight genomic DNA was isolated from the stabilized whole blood before PCR-free sequencing libraries were generated with sufficient yield for downstream sequencing. Whole genome sequencing (WGS) was performed on all 3 patients with genomic data passing quality assessment (QA) after alignment and variant calling (mean coverage >30x, alignment >97%, percent bases 20x >92%). For variant priorization and interpretation, we utilized a phenotype-aware workflow, Genomizer, with the gene ontology HP:0006633 and the parent ontology of “abnormality of the glenoid fossa.” Additionally, we interpreted variants from genes within the American College of Medical Genetics and Genomics (ACMG) v3.2 list, to potentially report actionable secondary findings.

HOXA9,c.715G>A:p.(Val239Met) was identified as a candidate genetic variant in 1 of 3 patients with severe glenoid dysplasia. Prior evidence has implicated the HOX gene in the development of the inferior glenoid ossification center. This information may lead to future precision medicine approaches for early diagnosis and novel treatments. Future larger studies are needed to confirm these findings.