Best, Robert G.Khushf, GeorgeRabin-Havt, Sara SchonfeldClayton, Ellen Wright...
3页
查看更多>>摘要：Disclaimer: This statement is designed primarily as an educational resource for medical geneticists and other clinicians to help them provide quality medical services. Adherence to this statement is completely voluntary and does not necessarily assure a successful medical outcome. This statement should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, clinicians should apply their own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. Clinicians are encouraged to document the reasons for the use of a particular procedure or test, whether or not it is in conformance with this statement. Clinicians also are advised to take notice of the date this statement was adopted, and to consider other medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.
Seaver, Laurie H.Khushf, GeorgeKing, Nancy M. P.Matalon, Dena R....
9页
查看更多>>摘要：Disclaimer: This statement is designed primarily as an educational resource for medical geneticists and other clinicians to help them provide quality medical services. Adherence to this statement is completely voluntary and does not necessarily assure a successful medical outcome. This statement should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, clinicians should apply their own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. Clinicians are encouraged to document the reasons for the use of a particular procedure or test, whether or not it is in conformance with this statement. Clinicians also are advised to take notice of the date this statement was adopted, and to consider other medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.
Britten-Jones, Alexis CeeceeJin, RuiGocuk, Sena A.Cichello, Elise...
14页
查看更多>>摘要：Purpose: This study aimed to systematically review and summarize gene therapy treatment for monogenic retinal and optic nerve diseases. Methods: This review was prospectively registered (CRD42021229812). A comprehensive literature search was performed in Ovid MEDLINE, Ovid Embase, Cochrane Central, and clinical trial registries (February 2021). Clinical studies describing DNA-based gene therapy treatments for monogenic posterior ocular diseases were eligible for inclusion. Risk of bias evaluation was performed. Data synthesis was undertaken applying Synthesis Without Meta-analysis guidelines. Results: This study identified 47 full-text publications, 50 conference abstracts, and 54 clinical trial registry entries describing DNA-based ocular gene therapy treatments for 16 different genetic variants. Study summaries and visual representations of safety and efficacy outcomes are presented for 20 unique full-text publications in RPE65-mediated retinal dystrophies, choroideremia, Leber hereditary optic neuropathy, rod-cone dystrophy, achromatopsia, and X-linked retinoschisis. The most common adverse events were related to lid/ocular surface/cornea abnormalities in subretinal gene therapy trials and anterior uveitis in intravitreal gene therapy trials. Conclusion: There is a high degree of variability in ocular monogenic gene therapy trials with respect to study design, statistical methodology, and reporting of safety and efficacy outcomes. This review improves the accessibility and transparency in interpreting gene therapy trials to date. (C) 2021 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.
Strnadova, IvaNevin, Suzanne M.Scully, Jackie LeachPalmer, Elizabeth E....
14页
查看更多>>摘要：Purpose: Genetic testing is frequently conducted on people with intellectual disability. This systematic literature review sought to assess what research has been conducted with people with intellectual disability to investigate their opinions and experiences of genetic counselling and testing. Methods: A search of 5 online databases (from year of database creation to 2021) yielded 1162 articles. Seven articles met the inclusion criteria. We assessed the quality, accessibility, and inclusivity of each study and extracted the data. Deductive content analysis was performed. Results: Most study participants showed both the desire and the capability to learn more about genetic conditions and genetic tests. Participants expressed a wide variety of opinions about genetic tests, similar to the range of opinions of the general population. All studies were small and were from a limited number of countries, and analysis showed limited evidence of inclusivity or accessibility. Conclusion: This review highlights major gaps in the understanding of the opinions, experiences, and preferences of people with intellectual disability regarding genetic counselling and testing. There is urgent need for research to codesign a more inclusive genomic model of care to address this failure in health care accessibility and equity. (C) 2021 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics.
查看更多>>摘要：Purpose: Conditions and thresholds applied for evidence weighting of within-codon concordance (PM5) for pathogenicity vary widely between laboratories and expert groups. Because of the sparseness of available clinical classifications, there is little evidence for variation in practice. Methods: We used as a truthset 7541 dichotomous functional classifications of BRCA1 and MSH2, spanning 311 codons of BRCA1 and 918 codons of MSH2, generated from large-scale functional assays that have been shown to correlate excellently with clinical classifications. We assessed PM5 at 5 stringencies with incorporation of 8 in silico tools. For each analysis, we quantified a positive likelihood ratio (pLR, true positive rate/false positive rate), the predictive value of PM5-lookup in ClinVar compared with the functional truthset. Results: pLR was 16.3 (10.6-24.9) for variants for which there was exactly 1 additional colocated deleterious variant on ClinVar, and the variant under examination was equally or more damaging when analyzed using BLOSUM62. pLR was 71.5 (37.8-135.3) for variants for which there were 2 or more colocated deleterious ClinVar variants, and the variant under examination was equally or more damaging than at least 1 colocated variant when analyzed using BLOSUM62. Conclusion: These analyses support the graded use of PM5, with potential to use it at higher evidence weighting where more stringent criteria are met. (C) 2021 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics.
Morgan, Kelly M.Hamilton, Jada G.Symecko, HeatherKamara, Daniella...
12页
查看更多>>摘要：Purpose: This study aimed to evaluate uptake and follow-up using internet-assisted population genetic testing (GT) for BRCA1/2 Ashkenazi Jewish founder pathogenic variants (AJPVs). Methods: Across 4 cities in the United States, from December 2017 to March 2020, individuals aged >= 25 years with >= 1 Ashkenazi Jewish grandparent were offered enrollment. Participants consented and enrolled online with chatbot and video education, underwent BRCA1/2 AJPV GT, and chose to receive results from their primary care provider (PCP) or study staff. Surveys were conducted at baseline, at 12 weeks, and annually for 5 years. Results: A total of 5193 participants enrolled and 4109 (79.1%) were tested (median age = 54, female = 77.1%). Upon enrollment, 35.1% of participants selected a PCP to disclose results, and 40.5% of PCPs agreed. Of those tested, 138 (3.4%) were AJPV heterozygotes of whom 21 (15.2%) had no significant family history of cancer, whereas 86 (62.3%) had a known familial pathogenic variant. At 12 weeks, 85.5% of participants with AJPVs planned increased cancer screening; only 3.7% with negative results and a significant family history reported further testing. Conclusion: Although continued follow-up is needed, internet-enabled outreach can expand access to targeted GT using a medical model. Observed challenges for population genetic screening efforts include recruitment barriers, improving PCP engagement, and increasing uptake of additional testing when indicated. (C) 2021 Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics.
查看更多>>摘要：Purpose: We aimed to investigate to what extent polygenic risk scores (PRS), rare pathogenic germline variants (PVs), and family history jointly influence breast cancer and prostate cancer risk. Methods: A total of 200,643 individuals from the UK Biobank were categorized as follows: (1) heterozygotes or nonheterozygotes for PVs in moderate to high-risk cancer genes, (2) PRS strata, and (3) with or without a family history of cancer. Multivariable logistic regression and Cox proportional hazards models were used to compute the odds ratio across groups and the cumulative incidence through life. Results: Cumulative incidence by age 70 years among the nonheterozygotes across PRS strata ranged from 9% to 32% and from 9% to 35% for breast cancer and prostate cancer, respectively. Among the PV heterozygotes it ranged from 20% to 48% in moderate-risk genes and from 51% to 74% in high-risk genes for breast cancer, and it ranged from 30% to 59% in prostate cancer risk genes. Family history was always associated with an increased cancer odds ratio. Conclusion: PRS alone provides a meaningful risk gradient leading to a cancer risk stratification comparable to PVs in moderate risk genes, whereas acts as a risk modifier when considering high-risk genes. Including family history along with PV and PRS further improves cancer risk stratification. (C) 2021 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics.
Zheng, WeiHartman, MikaelEaston, Douglas F.Teo, Soo-Hwang...
15页
查看更多>>摘要：Purpose: Non-European populations are under-represented in genetics studies, hindering clinical implementation of breast cancer polygenic risk scores (PRSs). We aimed to develop PRSs using the largest available studies of Asian ancestry and to assess the transferability of PRS across ethnic subgroups. Methods: The development data set comprised 138,309 women from 17 case-control studies. PRSs were generated using a clumping and thresholding method, lasso penalized regression, an Empirical Bayes approach, a Bayesian polygenic prediction approach, or linear combinations of multiple PRSs. These PRSs were evaluated in 89,898 women from 3 prospective studies (1592 incident cases). Results: The best performing PRS (genome-wide set of single-nucleotide variations [formerly single-nucleotide polymorphism]) had a hazard ratio per unit SD of 1.62 (95% CI = 1.46-1.80) and an area under the receiver operating curve of 0.635 (95% CI = 0.622-0.649). Combined Asian and European PRSs (333 single-nucleotide variations) had a hazard ratio per SD of 1.53 (95% CI = 1.37-1.71) and an area under the receiver operating curve of 0.621 (95% CI = 0.608-0.635). The distribution of the latter PRS was different across ethnic subgroups, confirming the importance of population-specific calibration for valid estimation of breast cancer risk. Conclusion: PRSs developed in this study, from association data from multiple ancestries, can enhance risk stratification for women of Asian ancestry. (C) 2021 by American College of Medical Genetics and Genomics. Published by Elsevier Inc.
查看更多>>摘要：Purpose: Genome-wide association studies have identified hundreds of single nucleotide variations (formerly single nucleotide polymorphisms) associated with several cancers, but the predictive ability of polygenic risk scores (PRSs) is unclear, especially among non-Whites. Methods: PRSs were derived from genome-wide significant single-nucleotide variations for 15 cancers in 20,079 individuals in an academic biobank. We evaluated the improvement in discriminatory accuracy by including cancer-specific PRS in patients of geneticallydetermined African and European ancestry. Results: Among the individuals of European genetic ancestry, PRSs for breast, colon, melanoma, and prostate were significantly associated with their respective cancers. Among the individuals of African genetic ancestry, PRSs for breast, colon, prostate, and thyroid were significantly associated with their respective cancers. The area under the curve of the model consisting of age, sex, and principal components was 0.621 to 0.710, and it increased by 1% to 4% with the inclusion of PRS in individuals of European genetic ancestry. In individuals of African genetic ancestry, area under the curve was overall higher in the model without the PRS (0.723-0.810) but increased by <1% with the inclusion of PRS for most cancers. Conclusion: PRS moderately increased the ability to discriminate the cancer status in individuals of European but not African ancestry. Further large-scale studies are needed to identify ancestryspecific genetic factors in non-White populations to incorporate PRS into cancer risk assessment. (c) 2021 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics.
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Elsevier