Most complex disease-associated genetic variants are located in non-coding regions and are therefore thought to be regulatory in nature. Association mapping of differential allelic expression (AE) is a powerful method to identify SNPs with direct cis-regulatory impact (cis-rSNPs). We used AE mapping to identify cis-rSNPs regulating gene expression in 55 and 63 HapMap lymphoblastoid cell lines from a Caucasian and an African population, respectively, 70 fibroblast cell lines, and 188 purified monocyte samples and found 40–60% of these cis-rSNPs to be shared across cell types. We uncover a new class of cis-rSNPs, which disrupt footprint-derived de novo motifs that are predominantly bound by repressive factors and are implicated in disease susceptibility through overlaps with GWAS SNPs. Finally, we provide the proof-of-principle for a new approach for genome-wide functional validation of transcription factor–SNP interactions. By perturbing NFκB action in lymphoblasts, we identified 489 cis-regulated transcripts with altered AE after NFκB perturbation. Altogether, we perform a comprehensive analysis of cis-variation in four cell populations and provide new tools for the identification of functional variants associated to complex diseases.

ObjectiveUp to 15% of patients with high-grade serous ovarian, tubal, or peritoneal carcinoma harbor a mutation in BRCA genes. Early notion of mutation status may facilitate counseling, predict prognosis, and increase access to Parp-inhibitors. The aim of this study was to examine the rate of germline genetic testing in a retrospective cohort of women with high-grade serous ovarian, tubal, or peritoneal carcinoma to determine if a new pilot project of gynecologic oncologist-initiated genetic testing improved the rate of testing, after 1 year of implementation.MethodsGynecologic oncology-initiated genetic testing was implemented at a single university hospital center with input and collaboration from gynecological oncologists, nurses, and genetic counselors. All patients diagnosed with high-grade serous ovarian, tubal, or peritoneal carcinoma after August 2017 were offered gynecologic oncologist- initiated genetic testing for a panel of 13 hereditary breast and ovarian cancer susceptibility genes. Data from this group was then compared with a historic cohort of patients who received traditional genetic counseling between January 2014 and August 2017 (control group). Patients that had genetic testing through a clinical trial were excluded. The primary outcome was the uptake of genetic testing in both groups. Secondary outcomes included difference in time from diagnosis to genetic result between both cohorts. Data was analyzed using SPSS 25.0 and medians (ranges) were reported.ResultsA total of 152 women with high-grade serous ovarian, tubal, or peritoneal carcinoma were included in this study. Between January 2014 to July 2017 there were 108 patients with high-grade serous ovarian, tubal, or peritoneal carcinoma, among which 50.9% (n=54) underwent genetic testing following referral to genetics. The prevalence of BRCA pathogenic variants was 25.9% (14/54): 9.2% (5/54) in BRCA1 and 16.7% (9/54) in BRCA2. The median time from diagnosis to genetics referral was 53 days (range; 3–751), and median time from diagnosis to test result disclosure was 186 days (range; 15–938). After 1 year of implementation of the gynecologic oncologist-initiated genetic testing model, among 44 women diagnosed with high-grade serous ovarian, tubal, or peritoneal carcinoma, 86.2% underwent genetic testing. The median time from diagnosis to result disclosure decreased to 58 days, representing a reduction of 128 days, or 4.27 months (P<0.001). Reasons for non-testing included refusal, death, and follow-up at another hospital. The prevalence of germline BRCA1/2 pathogenic variants was 21% (8/38).ConclusionGynecologic oncologist-initiated genetic testing at the time of high-grade serous ovarian, tubal, or peritoneal carcinoma diagnosis leads to increased uptake and decreased delays in testing compared with referral for traditional genetic counseling.

Background Sarcomas in adults can be associated with hereditary cancer syndromes characterized by early-onset

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A report on the 12th International Congress of Human Genetics, joint with the 61st annual American Society of Human Genetics conference, Montreal, Quebec, 11-15 October 2011.