A Systematic Genetic Assessment of ARFGEF2 Mutations in Periventricular Heterotopia

Mutations in ADP-ribosylation factor guanine nucleotide-exchange factor 2 (ARFGEF2) lead to autosomal recessive periventricular heterotopia (PH). To date, 11 mutations, (six missense mutations, one splicing mutation, one small deletion, two small insertions, and one small deletion/insertion) have been reported. Assessing ARFGEF2 mutations will provide a holistic overview of PH. This retrospective study was conducted in 2016 at King Faisal Specialist Hospital and Research Center. For the index patient, magnetic resonance imaging studies revealed a symmetrical focal hyperintensity involving the putamen bilaterally and the inner aspect of the globus pallidus. After family members were genotyped, an autozygosity analysis was performed, followed by exome sequencing of the index patient; A comprehensive filtering approach based on the loss of heterozygosity (LOH) was used to identify variants in phenotypically relevant genes. We report a consanguineous family with two affected individuals, a boy and a girl, with a history of microcephaly, global developmental delay, intellectual disability, myoclonic seizure, and dystonia. The patients carried a novel nonsense mutation (c.3974G>A, p. Trp1325*) in the Armadillo-type fold domain of ARFGEF2. These findings extend our understanding of the phenotype–genotype correlations for ARFGEF2 mutations.