Periventricular Heterotopia with Microcephaly via the ARFGEF2 Gene

Periventricular heterotopia with microcephaly (PHM) is a neuronal migration disorder with onset in the first 3-9 months of life. Early symptoms include severe hypotonia, feeding problems, acquired microcephaly and infantile spasms or absence seizures (Sheen et al. 2004). Seizures occur in most patients and can be refractory to treatment. EEGs show hypsarrhythmia or other epileptiform activity (Tanyalçin et al. 2013). PHM may evolve into other seizure disorders such as West or Lennox-Gastout syndromes (Banne et al. 2013). Another characteristic of PHM is severe developmental delay and/or developmental regression. PHM patients have profound intellectual disability with absence of speech and many cannot sit or stand unassisted. MRI in PHM patients reveals diffuse periventricular heterotopia, thin corpus callosum, and cortical and hippocampal atrophy (Sheen et al. 2004; Tanyalçin et al. 2013).

PHM can be caused by variants in the ARFGEF2 gene and is inherited in an autosomal recessive manner. Missense, splice site and frameshift variants in ARFGEF2 have been reported to be pathogenic (Sheen et al. 2004; de Wit et al. 2009; Banne et al. 2013). ARFGEF2 encodes the protein BIG2. ARFGEF proteins are guanine nucleotide exchange factors (GEF) which activate ADP-ribosylation factors (ARF) (de Wit et al. 2009). ARFs regulate vesicle and membrane trafficking from the trans-Golgi network. BIG2 is one of three ARFGEF proteins expressed in the brain during neuronal development and is enriched in the cortical ventricular zone. Periventricular heterotopia is caused by the abnormal positioning of post-mitotic neurons, which occurs as a result of defects in neuronal migration. The loss of BIG2 leads to endosome recycling defects and failure to deliver proteins to the cell membrane (de Wit et al. 2009). It is hypothesized that lack of receptors for signaling molecules, such as GABAA, in the brain in the absence of BIG2 underlie the neuronal migration defects seen in PHM patients (Sheen et al. 2004).

No large scale sequencing of ARFGEF2 in PHM patients has been performed, thus the clinical sensitivity of ARFGEF2 sequencing in PHM is currently unknown.

This test provides full coverage of all coding exons of the ARFGEF2 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).