A novel homozygous ARFGEF2 splice-site variant causing periventricular nodular heterotopia with microcephaly

Background The ARFGEF2 gene encodes the brefeldin A (BFA)-inhibited GEF2 protein (BIG2), which is distributed in the trans-Golgi network and plays a crucial role in neuronal proliferation and migration during cortical development through its regulation of vesicle transport. Pathogenic mutations in the ARFGEF2 gene are associated with autosomal recessive periventricular nodular heterotopia with microcephaly (ARPHM). To date, only slightly more than 20 cases have been reported worldwide. Herein, we presented a case of a patient with West syndrome who was ultimately diagnosed with ARPHM caused by a homozygous variant in the ARFGEF2 gene. Methods To identify disease-causing mutations, we performed exome sequencing (ES) of a child with West syndrome, and subsequently employed a minigene splicing assay to evaluate the functional impact of the ARFGEF2 gene splicing variant. Results The patient's clinical manifestations, examination results, treatment, and follow-up course were comprehensively documented. ES revealed a homozygous NM_006420.3: c.5181+1G>T variant in the ARFGEF2 gene. Subsequent functional analysis using a minigene splicing assay confirmed that this variant disrupts normal mRNA splicing, causing complete exon 38 skipping and a 118-bp deletion. The translation of this aberrant transcript is predicted to induce a frameshift, resulting in a truncated protein (p.Val1689SerfsTer20). Conclusion A novel pathogenic variant was identified by ES, and a minigene splicing assay established its disruptive impact on ARFGEF2 mRNA splicing. This study expands the genetic spectrum of ARFGEF2 and provides laboratory evidence for clinical diagnosis.