Clinical Features, Molecular Pathogenesis, Diagnosis and Management of Holt-oram Syndrome: A Narrative Review

Holt-Oram Syndrome (HOS) is a rare autosomal dominant disorder caused by mutations in the TBX5 gene, characterised by radial ray anomalies and congenital cardiac abnormalities. The syndrome, which was described by Holt and Oram in 1960 as a ‘heart-hand’ syndrome, presents with fully penetrant but variably expressive clinical features affecting the upper limbs and cardiovascular system. This review aims to provide a comprehensive updated overview of HOS regarding clinical spectrum, pathogenesis, diagnosis and differential diagnosis, management approach, along with some emerging therapies, with a highlight on the Indian scenario. This narrative review shows the latest information about the structural and functional roles of TBX5, modifier genes and environmental factors affecting HOS, and early diagnosis through prenatal imaging and molecular testing. Recent studies, like CRISPR/Cas9-engineered models and single-nucleus RNA sequencing, highlighted potential therapeutic targets with transcriptional disruptions. The article also explores Preimplantation Genetic Diagnosis (PGD) in preventing disease transmission and discusses the psychological and functional outcomes of patients with various severities of limb and cardiac involvement. This review is novel in the aspect of recent molecular and translational research with clinical management and prognosis, including some underreported Indian cases with unique challenges for diagnosis and management in such a low-resource healthcare scenario. It also shows the importance of multidisciplinary care and long-term follow-up in cardiac conduction anomalies of HOS. A detailed spectrum of clinical features, emerging therapeutic directions, presented in this review, aims to bridge previous knowledge gaps and also guides future research, clinical strategies for the improved care of individuals with HOS.