Novel Splice Site Variant in ARFGEF2: Expanding the Phenotypic Spectrum of Periventricular Heterotopia

Periventricular heterotopia (PH) is a rare developmental cause of intellectual disability (ID). One form is autosomal recessive PH with microcephaly (ARPHM), characterized by developmental delay and learning difficulties, with onset in infancy, plus recurrent seizures that onset in mid-adolescence. It is caused by biallelic variants in ARFGEF2. We report a consanguineous Pakistani family with three sibs afflicted with moderate/severe ID, developmental delay, muscle hypotonia, dystonia and contracture of distal limb joints, flat feet, and variable behavioral abnormalities. Single-nucleotide polymorphism (SNP)-based genotyping, homozygosity mapping, and genome sequencing (GS) were employed to genetically characterize the condition. This study shows that in addition to the characteristic features overlapping ARPHM, affected sibs have poor or no speech, enuresis, and encopresis. Pubertal onset was absent in females and delayed in the male, but they do not have the typical ARPHM symptoms of seizures, hypsarrhythmia, or microcephaly. The features were milder in the male patient. By homozygosity mapping coupled with genome sequencing, we identified a novel homozygous splicing variant, ARFGEF2 c.4455-1G>A, deduced to lead to skipping of exon 33 and deletion of the terminal 300 amino acids. We did not find any other candidate variant that could possibly underlie the additional clinical features in affected sibs. In conclusion, the high-throughput methods like SNP-based genotyping, coupled with GS, are very effective in reaching a robust molecular diagnosis. The affected sibs exhibit a variety of phenotypic features, which may be useful in the clinical delineation of this condition from other ID types.