In trans variant calling reveals enrichment for compound heterozygous variants in genes involved in neuronal development and growth.

Allison J Cox; Fillan Grady; Gabriel Velez; Vinit B Mahajan; Polly J Ferguson; Andrew Kitchen; Benjamin W Darbro; Alexander G Bassuk

In summary, we present a free tool VarCount for the quantification of qualifying mutations as an indicator function per individual in the analysis of variant lists (vcf files). We used VarCount to assess enrichment of rare, coding, compound heterozygous variants in a cohort of 264 epilepsy probands and found enrichment in three genes involved in neurodevelopmental processes -PRTG, TNC and MACF1. A missense change at the E104 residue of PRTG was identified three times in two different probands. Significance was not maintained after correction for multiple testing, and larger cohorts or candidate gene studies using a different sample set are necessary to validate this enrichment. In the context of the de novo mutations also present in these patients, experimentation is necessary in order to delineate if the compound heterozygous or de novo mutations, or both, are pathogenic in the development of epileptic encephalopathy. PRTG, TNC, and MACF1 are candidate recessive epilepsy genes and our work highlights that inheritance of compound heterozygous variants should not be excluded from gene discovery or diagnostic analyses of patients with epilepsy.