A Novel Pathogenic Variant in EXT1 Causing Autosomal Dominant Multiple Hereditary Exostoses in a 5-Year-Old Rwandan Patient

INTRODUCTION: Hereditary multiple osteochondromas (HMO) is a rare autosomal dominant skeletal disorder characterized by the development of multiple cartilage-capped bony outgrowths caused predominantly by pathogenic variants in the EXT1 or EXT2 genes. Although molecular diagnosis has become increasingly accessible worldwide, genetically confirmed cases from sub- Saharan Africa remain scarce, limiting knowledge of the regional mutational spectrum. CASE PRESENTATION: We report the case of a 5-year-old Rwandan girl who presented with progressively enlarging, painless bony swellings involving both knees and the right clavicle, accompanied by bilateral genu valgum. Radiographs demonstrated multiple osteochondromas affecting the distal femora, proximal tibiae, fibulae, and ulna, consistent with hereditary multiple osteochondromas. Conventional cytogenetic analysis showed a normal female karyotype (46,XX). Targeted next-generation sequencing identified a novel heterozygous frameshift variant in EXT1(NM_000127.2:c.640del; p.Ala214ArgfsTer38). The variant was absent from population databases and was classified as likely pathogenic according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria (PVS1 and PM2), confirming the diagnosis of autosomal dominant hereditary multiple osteochondromas type 1 (OMIM #133700). The patient was managed through a multidisciplinary team with orthopedic follow-up and genetic counseling. CONCLUSION: This report presents the first molecularly confirmed case of hereditary multiple osteochondromas in Rwanda, identifying a novel likely pathogenic EXT1 variant. It demonstrates the value of genomic testing for accurate diagnosis, multidisciplinary management, genetic counseling, and long-term surveillance, while expanding the representation of African populations in global genomic variant databases.