Expanded phenotype of new DOCK4-related neurodevelopmental disease in patient with pituitary stalk interruption syndrome and septo-optic dysplasia

Abstract Dedicator of Cytokinesis 4 (DOCK4) is increasingly recognized as being involved in human neurodevelopmental disorders. Because only a few cases have been reported, the full phenotypic spectrum remains poorly defined. We report a 17-year-old female patient with heterozygous truncating DOCK4 de novo variant NM_001363540.2:c.4651C > T (p.Arg1551*). She presented with global developmental delay, mild intellectual disability, microcephaly, ataxia and hypopituitarism. Brain magnetic resonance imaging showed pituitary stalk interruption syndrome (PSIS), features of septo-optic dysplasia (SOD) and polymicrogyria. Whole-exome sequencing identified the de novo DOCK4 variant, which is predicted to undergo nonsense-mediated mRNA decay and fulfilled PVS1 „very strong” criteria using the ClinGen/AutoPVS1 framework. Given the established role of DOCK4 in RAC1-mediated neurodevelopmental pathways, the identified loss-of-function variant is likely to contribute to the observed neurodevelopmental phenotype and may represent a candidate explanation for the associated structural brain abnormalities. This report expands the phenotypic spectrum of DOCK4-related neurodevelopmental disorder and raises the possibility that SOD and PSIS may represent previously unrecognized manifestations of DOCK4 deficiency.