Approaches to solving undiagnosed rare genetic diseases in consanguineous populations

Abstract

Rare genetic diseases present with a broad spectrum of clinical manifestations, frequently affecting multiple organ systems or causing isolated, severe physical impairments. These disorders represent a profound public health and socioeconomic burden due to prolonged diagnostic delays, suboptimal clinical management, and the lack of targeted therapeutic options. While early detection remains paramount to establishing effective clinical care, rehabilitation protocols, and orthopedic interventions, the molecular etiologies of numerous musculoskeletal, neurodevelopmental, and immunological rare conditions remain completely unknown. Key drivers of this diagnostic gap include fragmented healthcare access, high costs of advanced genomic technologies, and a lack of integrated research pipelines capable of translating variants of uncertain significance into confirmed disease-causing genes. Identifying and functionally validating these genetic factors is essential for expanding the known Mendeliome, discovering novel diagnostic biomarkers, and revealing targetable pathways for future therapeutics. In this review, using an implementation model, we evaluate the global and regional burdens of undiagnosed rare genetic diseases and outline a strategic, multi-omics functional workflow tailored to address complex, hidden variants in the highly consanguineous population of Saudi Arabia.