The International Registry of Werner syndrome (www.wernersyndrome.org) has been providing molecular diagnosis of the Werner syndrome (WS) for the past decade. The present communication summarizes, from among 99 WS subjects, the spectrum of 50 distinct mutations discovered by our group and by others since the WRN gene (also called RECQL2 or REQ3) was first cloned in 1996; 25 of these have not previously been published. All WRN mutations reported thus far have resulted in the elimination of the nuclear localization signal at the C-terminus of the protein, precluding functional interactions in the nucleus; thus, all could be classified as null mutations. We now report two new mutations in the N-terminus that result in instability of the WRN protein. Clinical data confirm that the most penetrant phenotype is bilateral ocular cataracts. Other cardinal signs were seen in more than 95% of the cases. The median age of death, previously reported to be in the range of 46-48 years, is 54 years. Lymphoblastoid cell lines (LCLs) have been cryopreserved from the majority of our index cases, including material from nuclear pedigrees. These, as well as inducible and complemented hTERT (catalytic subunit of human telomerase) immortalized skin fibroblast cell lines are available to qualified investigators.
The development and usage of two companion NIH-funded genetic testing information databases, GeneTests (www.genetests.org) and GeneClinics (www.geneclinics.org), now merged into one web site, reflect the steadily increasing use of genetic testing and the expanding audience for genetic testing information. Established in 1993 as Helix, a genetics laboratory directory of approximately 110 listings, GeneTests has grown into a database of over 900 tests for inherited diseases, a directory of over 500 international laboratories, a directory of over 1,000 U.S. and international genetics clinics, and a resource for educational/teaching materials and reports of summary genetic test data. GeneClinics, founded in 1997 as an expert-authored, peer-reviewed, disease-specific knowledge base relating genetic testing to patient care, has grown steadily, now containing over 130 expert-authored, peer-reviewed full-text entries relating genetic testing information to diagnosis, management, and genetic counseling of specific inherited diseases. In spring 2001 the two databases were merged and in October 2001 the two web sites were merged for the purpose of seamless navigation into the GeneTests-GeneClinics site (www.genetests.org or www.geneclinics.org); the GeneClinics knowledge base was renamed "GeneReviews" to avoid confusion with the U.S. and international clinic directories. As genetic testing has moved steadily out of research venues and into routine medical practice, the user audience for these databases has become international and expansive and includes healthcare providers, patients, educators, policy makers, and the media. The use of these combined resources has grown to approximately 3,200 visits/day.
Objective We sought to determine whether prophylactic oophorectomy rates changed after the introduction of a 2007 health plan clinical guideline recommending systematic referral to a genetic counselor for women with a personal or family history suggestive of an inherited susceptibility to breast/ovarian cancer. Methods We conducted a retrospective cohort study of female members of Group Health, an integrated delivery system in Washington State. Subjects were women aged ≥35 years during 2004–2009 who reported a personal or family history consistent with an inherited susceptibility to breast/ovarian cancer. Personal and family history information was collected on a questionnaire completed when the women had a mammogram. We ascertained oophorectomies from automated claims data and determined whether surgeries were prophylactic by medical chart review. Rates were age-adjusted and age-adjusted incidence rate ratios (IRR) and 95% confidence intervals (CI) were computed using Poisson regression. Results Prophylactic oophorectomy rates were relatively unchanged after compared to before the guideline change, 1.0 versus 0.8/1,000 person-years, (IRR = 1.2; 95% CI: 0.7–2.0), whereas bilateral oophorectomy rates for other indications decreased. Genetic counseling receipt rates doubled after the guideline change (95% CI: 1.7–2.4) from 5.1 to 10.2/1,000 person-years. During the study, bilateral oophorectomy rates were appreciably greater in women who saw a genetic counselor compared to those who did not regardless of whether they received genetic testing as part of their counseling. Conclusion A doubling in genetic counseling receipt rates lends support to the idea that the guideline issuance contributed to sustained rates of prophylactic oophorectomies in more recent years.
Background Guidelines recommend genetic counseling and testing for women with a pedigree suggestive of an inherited susceptibility for ovarian cancer. We evaluated the effect of referral to genetic counseling on genetic testing and prophylactic oophorectomy via a randomized controlled trial. Methods Data from an electronic mammography reporting system identified 12,919 women with a pedigree including breast cancer, of whom 625 were identified as high risk for inherited susceptibility to ovarian cancer using a risk assessment questionnaire. Of these, 458 women provided informed consent and were randomized 1:1 to intervention consisting of a genetic counseling referral (n=228) or standard clinical care (n=230). Results Participants were predominantly aged 45 to 65; 30% and 20% reported a personal history of breast cancer or a family history of ovarian cancer, respectively. Eighty-five percent of women in the intervention group participated in a genetic counseling session. Genetic testing was reported by 74 (33%) and 20 (9%) women in the intervention and control arms (p<0.005) respectively. Five women in the intervention arm and two women in the control arm were identified as germline mutation carriers. Ten women in the intervention arm and three women in the control arm underwent prophylactic BSO (p<0.05). Conclusion Routine referral of women at high risk for ovarian cancer to genetic counseling promotes genetic testing and prophylactic surgery. Our findings from a randomized controlled trial demonstrate the value of implementing strategies targeting women at high risk for ovarian cancer to ensure they are offered access to recommended care.
Women with a documented deleterious mutation in BRCA1 or BRCA2 are at substantially elevated risk for ovarian cancer. To understand what percentage of women with high risk family histories know their risk is elevated we surveyed 1,885 women with a high or moderate risk family history and no personal history of breast or ovarian cancer, and asked about their perceived risk of breast and ovarian cancer. Among high-risk women, fewer than 20% reported use of genetic counseling, and knowledge of elevated risk of ovarian cancer was low. Prior genetic counseling was associated with greater perceived risk for ovarian cancer. Results suggest that most high-risk women (> 75%) do not know their risk for ovarian cancer. Identification of potentially high-risk women for referral to genetic counseling may improve informed ovarian cancer risk management.
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