GIT1 loss of function causes a recognizable syndromic neurodevelopmental disorder

The G-protein-coupled receptor kinase-interacting protein 1, GIT1, is a multifunctional scaffold protein that plays key roles in the regulation of actin cytoskeletal dynamics, focal adhesion assembly, membrane trafficking, and intracellular signaling. In mice, loss of Git1 function causes a microcephaly-like phenotype characterized by a smaller brain due to reduced neuronal cell size, accompanied by behavioral deficits, altered gait, and impairment in motor coordination, learning and memory. To date, variants in GIT1 have not been definitely linked to human disease. By applying a combined genomic approach based on linkage analysis and exome sequencing, we provide evidence that biallelic GIT1 variants affecting transcript processing or causing premature termination underlie a syndromic neurodevelopmental disorder. Nine affected individuals from three families were identified to share a clinically homogeneous syndromic phenotype with major features including microcephaly, brain MRI anomalies, developmental delay/intellectual disability, a recognizable facial gestalt, and intrauterine growth restriction with postnatal growth failure. We used complementary in vitro and in vivo approaches to validate this causal relationship. Cell-based functional analyses using patient-derived fibroblasts confirmed the inactivating behavior of the disease-associated variants and demonstrated that loss of GIT1 function disrupts actin cytoskeleton dynamics, leading to defective cell spreading and flawed formation of focal adhesions as a result of reduced RAC1 activation. A zebrafish git1 knockdown model recapitulated the clinical phenotype observed in affected patients and further validated the loss-of-function effect of the identified variants. Collectively, our findings establish an essential role for GIT1 in development and cognitive function.