BACKGROUND Family history is a significant risk factor for prostate cancer, although the molecular basis for this association is poorly understood. Linkage studies have implicated chromosome 17q21-22 as a possible location of a prostate-cancer susceptibility gene. METHODS We screened more than 200 genes in the 17q21-22 region by sequencing germline DNA from 94 unrelated patients with prostate cancer from families selected for linkage to the candidate region. We tested family members, additional case subjects, and control subjects to characterize the frequency of the identified mutations. RESULTS Probands from four families were discovered to have a rare but recurrent mutation (G84E) in HOXB13 (rs138213197), a homeobox transcription factor gene that is important in prostate development. All 18 men with prostate cancer and available DNA in these four families carried the mutation. The carrier rate of the G84E mutation was increased by a factor of approximately 20 in 5083 unrelated subjects of European descent who had prostate cancer, with the mutation found in 72 subjects (1.4%), as compared with 1 in 1401 control subjects (0.1%) (P = 8.5×10−7). The mutation was significantly more common in men with early-onset, familial prostate cancer (3.1%) than in those with late-onset, nonfamilial prostate cancer (0.6%) (P = 2.0×10−6). CONCLUSIONS The novel HOXB13 G84E variant is associated with a significantly increased risk of hereditary prostate cancer. Although the variant accounts for a small fraction of all prostate cancers, this finding has implications for prostate-cancer risk assessment and may provide new mechanistic insights into this common cancer. (Funded by the National Institutes of Health and others.)

Purpose Next-generation sequencing (NGS) has transformed genetic research and is poised to revolutionize clinical diagnosis. However, the vast amount of data and inevitable discovery of incidental findings require novel analytic approaches. We therefore implemented for the first time a strategy that utilizes an a priori structured framework and a conservative threshold for selecting clinically relevant incidental findings. Methods We categorized 2016 genes linked with Mendelian diseases into “bins” based on clinical utility and validity, and used a computational algorithm to analyze 80 whole genome sequences in order to explore the use of such an approach in a simulated real-world setting. Results The algorithm effectively reduced the number of variants requiring human review and identified incidental variants with likely clinical relevance. Incorporation of the Human Gene Mutation Database (HGMD) improved the yield for missense mutations, but also revealed that a substantial proportion of purported disease-causing mutations were misleading. Conclusions This approach is adaptable to any clinically relevant bin structure, scalable to the demands of a clinical laboratory workflow, and flexible with respect to advances in genomics. We anticipate that application of this strategy will facilitate pre-test informed consent, laboratory analysis, and post-test return of results in a clinical context.

PurposeWe investigated the diagnostic and clinical performance of exome sequencing (ES) in fetuses with sonographic abnormalities with normal karyotype, microarray and, in some cases, normal gene specific sequencing.MethodsES was performed from DNA of 15 anomalous fetuses and from peripheral blood from their parents. Parents provided consent for the return of diagnostic results in the fetus, medically actionable findings in the parents, and identification as carrier couple for significant autosomal recessive conditions. We assessed perceptions and understanding of ES with mixed-methods in 15 mother-father dyads.ResultsIn 7 (47%) of 15 fetuses, ES provided a diagnosis or possible diagnosis with identification of variants in the following genes: COL1A1, MUSK, KCTD1, RTTN, TMEM67, PIEZO1; and DYNC2H1. One additional case revealed a de novo nonsense mutation in a novel candidate gene (MAP4K4). The perceived likelihood that ES would explain the results (5.2/10) was higher than the approximately 30% diagnostic yield discussed in pre-test counseling.ConclusionsES has diagnostic utility in a highly select population of fetuses where a genetic diagnosis was highly suspected. Challenges related to genetics literacy, and variant interpretation must be addressed by highly tailored pre- and post-test genetic counseling.