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

The primary publication reporting analysis of the Epi4k trio dataset was a description of de novo mutations in the probands (Epi et al., 2013 ). An analysis of compound heterozygous variants was also reported, using a minor allele frequency cutoff of 0.15%, which is lower than the cutoff used in the work presented here. In this analysis, the parents were used as internal controls, and compound heterozygous variants in 351 genes were identified, without genome-wide significance. The authors only listed five of the genes which are known to cause Mendelian disorders that include a seizure phenotype -ASPM, CNTNAP2, GPR98, PCNT, and POMGNT1. In our analysis using the 1000 genomes participants as controls, enrichment for compound heterozygous variants was not detected in any of these genes. Using the number of individuals with in trans variants in a gene (transcript) as an indicator function required at least two probands to have qualifying variants in order to detect single-test significance, with complete absence of qualifying variants in controls. It is clear from the analyses using either internal controls or the 1000 genomes as controls that a larger sample size is required to achieve genome-wide significance.