TRIO and Macrocephaly: In this context, pathogenic variants in TRIO, encoding a GEF which activates RAC1 through the first GEF domain (GEFD1), were shown to cause neurodevelopmental impairment, behavioural disturbances, microcephaly or macrocephaly and skeletal features [autosomal dominant intellectual developmental disorder with microcephaly (MRD44, OMIM 617061) or macrocephaly (MRD63, OMIM 618825)].62,63 Affected individuals with variations in TRIO present with variable neurodevelopmental phenotypes.