No abstract

Family history is increasingly important in primary care as a means to detect candidates for genetic testing or tailored prevention programs. We evaluated primary care physicians' skills in assessing family history for breast cancer risk, using unannounced standardized patient visits to 86 general internists and family medicine practitioners in King County, WA. Transcripts of clinical encounters were coded to determine ascertainment of family history, risk assessment, and clinical follow-up. Physicians in our study collected sufficient family history to assess breast cancer risk in 48% of encounters with an anxious patient at moderate risk, 100% of encounters with a patient who had a strong maternal family history of breast cancer, and 45% of encounters with a patient who had a strong paternal family history of breast and ovarian cancer. Increased risk was usually communicated in terms of recommendations for preventive action. Few physicians referred patients to genetic counseling, few associated ovarian cancer with breast cancer risk, and some incorrectly discounted paternal family history of breast cancer. We conclude that pedigree assessment of breast cancer risk is feasible in primary care, but may occur consistently only when a strong maternal family history is present. Primary care education should focus on the link between inherited breast and ovarian cancer risk and on the significance of paternal family history. Educational efforts may be most successful when they emphasize the value of genetic counseling for individuals at risk for inherited cancer and the connection between genetic risk and specific prevention measures.

Individualized interpretation of gene panels is a complex medical activity. Interpretation by multiple experts in the context of personal and family histories maximizes actionable results and minimizes reports of VUS.Genet Med 18 10, 974-981.

Pediatric cataracts are observed in 1–15 per 10,000 births with 10–25% of cases attributed to genetic causes; autosomal dominant inheritance is the most commonly observed pattern. Since the specific cataract phenotype is not sufficient to predict which gene is mutated, whole exome sequencing (WES) was utilized to concurrently screen all known cataract genes and to examine novel candidate factors for a disease-causing mutation in probands from 23 pedigrees affected with familial dominant cataract. Review of WES data for 36 known cataract genes identified causative mutations in nine pedigrees (39%) in CRYAA, CRYBB1, CRYBB3, CRYGC (2), CRYGD, GJA8 (2), and MIP and an additional likely causative mutation in EYA1; the CRYBB3 mutation represents the first dominant allele in this gene and demonstrates incomplete penetrance. Examination of crystallin genes not yet linked to human disease identified a novel cataract gene, CRYBA2, a member of the βγ-crystallin superfamily. The p.(Val50Met) mutation in CRYBA2 cosegregated with disease phenotype in a four-generation pedigree with autosomal dominant congenital cataracts with incomplete penetrance. Expression studies detected cryba2 transcripts during early lens development in zebrafish, supporting its role in congenital disease. Our data highlight the extreme genetic heterogeneity of dominant cataract as the eleven causative/likely causative mutations affected nine different genes and the majority of mutant alleles were novel. Furthermore, these data suggest that less than half of dominant cataract can be explained by mutations in currently known genes.

No abstract