Genomic Confluence: When Cerebrotendinous Xanthomatosis, Klinefelter Syndrome, and a BRCA2 Variant Intersect

Multilocus pathogenic variation—when multiple genetic disorders coexist in a single individual—remains rare but is increasingly recognized in the era of genomic medicine. Reporting such cases is essential to improve diagnostic accuracy, refine clinical management, and inform genetic counseling. We describe a pediatric case with three distinct genetic diagnoses contributing to an atypical and complex phenotype. The patient was born to consanguineous parents, presented with neurological symptoms, gastrointestinal dysfunction, endocrine abnormalities, and dysmorphic features. Trio-based exome sequencing identified three independent findings: cerebrotendinous xanthomatosis (CTX) due to a homozygous pathogenic variant in the cytochrome P450 family 27 subfamily A member 1 (CYP27A1) gene, Klinefelter syndrome (47,XXY), and an incidental heterozygous pathogenic variant in the breast cancer 2 susceptibility gene (BRCA2), associated with hereditary cancer predisposition. The overlapping manifestations of CTX and Klinefelter syndrome produced a non-classical presentation that delayed diagnosis. The BRCA2 variant, though unrelated to presenting symptoms, has major implications for future cancer surveillance and family risk assessment. This case underscores the utility of exome sequencing in elucidating complex phenotypes, particularly in consanguineous populations, and highlights the need for multidisciplinary care and tailored guidelines for patients with multiple genetic diagnoses, including the management of incidental findings with actionable implications.