DYNC1H1 in Spinal Muscular Atrophy: Diagnostic Findings From Two Families and a Comprehensive Review of Its Role in Neuromuscular and Neurodevelopmental Disorders.

BACKGROUND: DYNC1H1 is a critical gene implicated in neurodevelopmental and neuromuscular disorders with overlapping and variable phenotypes that challenge diagnosis. METHODS AND RESULTS: Whole exome sequencing in patients presenting with motor neuron disease symptoms and a predominant pattern of lower-limb muscle weakness revealed pathogenic DYNC1H1 variants. This expands the known phenotypic spectrum to include rare features such as scapular winging and camptocormia. Clinical evaluations of affected individuals revealed features consistent with SMA-LED, reinforcing the role of DYNC1H1 in neuromuscular disorders. A review of 208 published DYNC1H1 variants highlighted significant clustering in the tail domain, primarily associated with neuromuscular conditions like SMA-LED. Approximately 28% of variants exhibited overlapping neuromuscular and neurodevelopmental features, emphasizing the diagnostic challenges posed by phenotypic overlap. These findings underscore the necessity of comprehensive clinical and genetic evaluations to address the variability observed within families and improve genotype-phenotype correlations. CONCLUSION: This study reinforces the importance of DYNC1H1 in motor neuron function and its pivotal role in neurodevelopmental and neuromuscular disease mechanisms. The integration of exome sequencing in clinical practice is essential for identifying rare and novel variants, enhancing diagnostic accuracy. We recommend incorporating DYNC1H1 screening into diagnostic workflows to advance understanding and management of conditions with overlapping phenotypes.