GIT1 loss of function causes a recognizable syndromic neurodevelopmental disorder

Biallelic *GIT1* variants affecting splicing or truncating, disrupting actin cytoskeleton dynamics via reduced RAC1 activation

A combined linkage and exome sequencing approach established that biallelic GIT1 variants, encoding a scaffold protein regulating actin cytoskeleton dynamics, underlie a syndromic neurodevelopmental disorder. Nine individuals from three families shared a homogeneous phenotype: microcephaly, brain MRI anomalies, developmental delay/intellectual disability, a recognizable facial gestalt, and intrauterine growth restriction with postnatal growth failure. Patient-derived fibroblasts confirmed the inactivating effect of the variants and disrupted actin cytoskeleton dynamics with reduced RAC1 activation. A zebrafish git1 knockdown model recapitulated the phenotype, validating loss of function.

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The causal demonstration is exemplary: familial recurrence, recognizable gestalt, concordant fibroblast functional data and zebrafish model. GIT1 joins the growing list of neurodevelopmental actinopathy genes and is immediately clinically recognizable, facilitating variant interpretation on exome/genome. Publication in Brain reflects the strength of the work.