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

Of the de novo variants reported in these genes, the nonsense variant in CELSR1 identified in one of the probands with in trans PRTG variants is the most likely to be pathogenic. However, regarding their involvement in neural tube defects, mutations in CELSR1 are thought to contribute to pathogenesis but not in a Mendelian fashion, as variants have been found to be inherited from unaffected parents or to be ineffective in functional assays (Robinson et al., 2012; Allache et al., 2012) . The nonsense CELSR1 mutation in the patient reported here may contribute to epilepsy in the presence of a genetic modifier. The de novo missense mutation in DIP2C is predicted to be deleterious (CADD = 23.6) and has a low rate of benign missense variation based on constraint metrics (z = 5.82). The de novo variant in GLRA2 is in the 3'UTR so it is difficult to predict its impact on gene function and subsequent pathogenicity.