Epilepsy: Early Infantile Epileptic Encephalopathy via the ARHGEF9 Gene

Early Infantile Epileptic Encephalopathy (EIEE) is a clinically and genetically heterogeneous neurodevelopmental disorder. The key feature of EIEE is onset of frequent and/or severe seizures within the first few weeks of life (Noh et al., 2012. PubMed ID: 22342633).

ARHGEF9-related early infantile epileptic encephalopathy is a rare genetic cause for early infantile epilepsy with onset at birth or early infancy. The common symptoms of this disorder include delayed motor development, severe tonic and hyperekplectic seizures, hypertonia, intellectual disability and a particular facial dysmorphic feature. Brain MRI shows normal or brain atrophy, hypoplastic frontal lobe, hippocampal sclerosis, frontal polymicrogyria in the patients. Male patients have severe symptoms, whereas heterozygous females are unaffected (Shimojima et al., 2011. PubMed ID: 21633362). However, female cases with intellectual disability have been reported due to de novo large deletions or translocations or inversions that interrupt the ARHGEF9 gene and skewed X inactivation. Patients have variable responses to antiepileptic drugs (Alber et al., 2017. PubMed ID: 28589176; Shimojima et al., 2011. PubMed ID: 21633362; Marco et al., 2009. PubMed ID: 21731583).

ARHGEF9-related early infantile epileptic encephalopathy is inherited in an X-linked recessive manner. It is caused by pathogenic variants in the ARHGEF9 gene encoding collybistin, a brain-specific GDP/GTP-exchange factor. Collybistin is required for both the initial formation and maintenance of gephyrin and gephyrin-dependent GABA_A receptor clusters at inhibitory post-synapses in certain regions of the forebrain (Papadopoulos and Soykan, 2011. PubMed ID: 21738498).

Pathogenic variants in ARHGEF9 include missense, nonsense, splicing variants, large deletions and complex rearrangements involving the ARHGEF9 locus (Human Gene Mutation Database; Alber et al., 2017. PubMed ID: 28589176). De novo pathogenic variants in ARHGEF9 gene are common and include point variants, large deletions, translocations, and inversions (Alber et al., 2017. PubMed ID: 28589176).

In one study of males with severe intellectual disability (ID) and epilepsy of unknown cause, 4% (1 in 23) of cases were found to be caused by single nucleotide variations in ARHGEF9 (Shimojima et al., 2011. PubMed ID: 21633362). Another study of males and females with ID of unknown cause identified pathogenic ARHGEF9 variants in 4% of males (2 of 47) (de Ligt et al., 2012. PubMed ID: 23033978).

In a review of the phenotypic and genotypic spectrum of ARHGEF9 pathogenic variants, 7 out of 18 cases were found to be caused by large deletions, inversions, translocations or other complex arrangements involving ARHGEF9 (Alber et al., 2017. PubMed ID: 28589176).

This test provides full coverage of all coding exons of the ARHGEF9 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.