Correct family segregation and somatic studies were used to categorize the most interesting variants in CDKN1B, XRCC4, EPHX1, NFKBIZ, SMARCA4, and BARD1.
Combining both types of features provides a quick and low-cost way to pinpoint the potentially most interesting variants for downstream validation and functional studies.
In addition, data from 183 breast tissues in the GTEx (V6) (2015) publically available online databases were evaluated to obtain information on whether the most interesting variants (rs1905339, rs8074296, rs146170568, chr17:40607850:I and rs77942990) were expression quantitative trait loci (eQTL) for any gene.
Most interesting, this genetic variant interacts with whether a person experienced abuse or neglect in their childhood, demonstrating that genes interact with environment.
ΔNΔC-VEGF-C therefore represents the most interesting VEGF-C variant to block.
Also, we limited our exon skipping candidate list to the variants with undisturbed ORFs, aiming to narrow it to the most interesting functional splice variants.
The most interesting of these variants was a heterozygous nonsense mutation (not found in 252 controls) which yielded a stop codon at position 328 of the FOXP2 protein, resulting in either a truncated protein missing the functionally important forkhead, leucine zipper and zinc finger domains or a complete loss of FOXP2 due to nonsense mediated RNA decay.
Of seven such variants, the most interesting candidate was a missense variant in N4BP3, a gene recently reported to be required for normal neuronal axonal branching (41).
A mutation in the BMP4 coding region resulting in an amino acid exchange (p.Arg300Pro) appeared most interesting among the identified variants.
The most interesting of the identified variants were identified in patients for which we did not have access to DNA from parents and/or other relatives, hence, we do not know how these alleles are transmitted or whether they have appeared de novo in the patients.
