Case report: Expanding the phenotype of mutations from increased intracranial aneurysm risk to a neurodevelopmental disease.

RhoGTPase regulators play a key role in the development of the nervous system, and their dysfunction can result in brain malformation and associated disorders. Several guanine nucleotide exchange factors (GEF) have been linked to neurodevelopmental disorders. In line with this, ARHGEF17 has been recently linked as a risk gene to intracranial aneurysms. Here we report siblings of a consanguineous Pakistani family with biallelic variants in the gene associated with a neurodevelopmental disorder with intellectual disability, speech delay and motor dysfunction but not aneurysms. Cranial MRI performed in one patient revealed generalized brain atrophy with an enlarged ventricular system, thin corpus callosum and microcephaly. Whole exome sequencing followed by Sanger sequencing in two of the affected individuals revealed a homozygous missense variant (g.11:73021307, c.1624C>T (NM_014786.4), p.R542W) in the gene. This variant is in a highly conserved DCLK1 phosphorylation consensus site (I/L/V/F/M]RRXX[pS/pT][I/L/M/V/F) of the protein. Our report expands the phenotypic spectrum of variants from increased intracranial aneurysm risk to neurodevelopmental disease and thereby add to the list of GEF genes involved in neurodevelopmental disorders.