Biallelic variants inARHGAP19cause a motor-predominant neuropathy with asymmetry and conduction slowing

Charcot-Marie-Tooth Disease is a clinically and genetically heterogeneous group of hereditary neuropathies, with over 100 causative genes identified to date. Despite progress in genetic sequencing, around a quarter of patients remain unsolved. Through international collaborations, we identified 16 recessive variants in Rho GTPase activating protein 19 ( ARHGAP19 ) causing motor-predominant neuropathy with conduction slowing in 25 individuals from 20 unrelated multi-ancestry families. ARHGAP19 is a GTPase-activating protein with activity towards RhoA. In vitro biochemical assays revealed that variants located within the GAP domain cause loss of GAP activity. iPSc-derived motor neurons exhibited 50% knockdown of ARHGAP19 protein. In vivo genetic perturbations of the Drosophila melanogaster ARHGAP19 ortholog RhoGAP54D reduced self-driven locomotor activity and startle responses to visual stimuli. Zebrafish loss-of-function models similarly exhibited movement deficits, coupled with increased motor neuron axonal branching but shorter caudal primary motor neurons. Together, these findings establish ARHGAP19 as a novel cause of early-onset neuropathy through a loss-of-function mechanism.