@article {46,
	title = {Modified penetrance of coding variants by cis-regulatory variation contributes to disease risk.},
	journal = {Nat Genet},
	volume = {50},
	year = {2018},
	month = {2018 Sep},
	pages = {1327-1334},
	abstract = {<p>Coding variants represent many of the strongest associations between genotype and phenotype; however, they exhibit inter-individual differences in effect, termed {\textquoteright}variable penetrance{\textquoteright}. Here, we study how cis-regulatory variation modifies the penetrance of coding variants. Using functional genomic and genetic data from the Genotype-Tissue Expression Project (GTEx), we observed that in the general population, purifying selection has depleted haplotype combinations predicted to increase pathogenic coding variant penetrance. Conversely, in cancer and autism patients, we observed an enrichment of penetrance increasing haplotype configurations for pathogenic variants in disease-implicated genes, providing evidence that regulatory haplotype configuration of coding variants affects disease risk. Finally, we experimentally validated this model by editing a Mendelian single-nucleotide polymorphism (SNP) using CRISPR/Cas9 on distinct expression haplotypes with the transcriptome as a phenotypic readout. Our results demonstrate that joint regulatory and coding variant effects are an important part of the genetic architecture of human traits and contribute to modified penetrance of disease-causing variants.</p>},
	issn = {1546-1718},
	doi = {10.1038/s41588-018-0192-y},
	author = {Castel, Stephane E and Cervera, Alejandra and Mohammadi, Pejman and Aguet, Fran{\c c}ois and Reverter, Ferran and Wolman, Aaron and Guigo, Roderic and Iossifov, Ivan and Vasileva, Ana and Lappalainen, Tuuli}
}
@article {10,
	title = {Genome Sequencing of Autism-Affected Families Reveals Disruption of Putative Noncoding Regulatory DNA.},
	journal = {Am J Hum Genet},
	volume = {98},
	year = {2016},
	month = {2016 Jan 07},
	pages = {58-74},
	abstract = {<p>We performed whole-genome sequencing (WGS) of 208 genomes from 53 families affected by simplex autism. For the majority of these families, no copy-number variant (CNV) or candidate de novo gene-disruptive single-nucleotide variant (SNV) had been detected by microarray or whole-exome sequencing (WES). We integrated multiple CNV and SNV analyses and extensive experimental validation to identify additional candidate mutations in eight families. We report that compared to control individuals, probands showed a significant (p = 0.03) enrichment of de novo and private disruptive mutations within fetal CNS DNase I hypersensitive sites (i.e., putative regulatory regions). This effect was only observed within 50 kb of genes that have been previously associated with autism risk, including genes where dosage sensitivity has already been established by recurrent disruptive de novo protein-coding mutations (ARID1B, SCN2A, NR3C2, PRKCA, and DSCAM). In addition, we provide evidence of gene-disruptive CNVs (in DISC1, WNT7A, RBFOX1, and MBD5), as well as smaller de novo CNVs and exon-specific SNVs missed by exome sequencing in neurodevelopmental genes (e.g., CANX, SAE1, and PIK3CA). Our results suggest that the detection of smaller, often multiple CNVs affecting putative regulatory elements might help explain additional risk of simplex autism.</p>},
	keywords = {Autistic Disorder, DNA, Exome, Female, Genome, Human, Humans, Male, Pedigree, Polymorphism, Single Nucleotide},
	issn = {1537-6605},
	doi = {10.1016/j.ajhg.2015.11.023},
	author = {Turner, Tychele N and Hormozdiari, Fereydoun and Duyzend, Michael H and McClymont, Sarah A and Hook, Paul W and Iossifov, Ivan and Raja, Archana and Baker, Carl and Hoekzema, Kendra and Stessman, Holly A and Zody, Michael C and Nelson, Bradley J and Huddleston, John and Sandstrom, Richard and Smith, Joshua D and Hanna, David and Swanson, James M and Faustman, Elaine M and Bamshad, Michael J and Stamatoyannopoulos, John and Nickerson, Deborah A and McCallion, Andrew S and Darnell, Robert and Eichler, Evan E}
}
