Penetrance Of Pathogenic Variants Research Articles

Screening for Rare Coding Variants That Associate With the QTc Interval in Iceland.

Background Long-QT syndrome (LQTS) is a cardiac repolarization abnormality that can lead to sudden cardiac death. The most common causes are rare coding variants in the genes KCNQ1, KCNH2, and SCN5A. The data on LQTS epidemiology are limited, and information on expressivity and penetrance of pathogenic variants is sparse. Methods and Results We screened for rare coding variants associated with the corrected QT (QTc) interval in Iceland. We explored the frequency of the identified variants, their penetrance, and their association with severe events. Twelve variants were associated with the QTc interval. Five in KCNQ1, 3 in KCNH2, 2 in cardiomyopathy genes MYBPC3 and PKP2, and 2 in genes where coding variants have not been associated with the QTc interval, ISOC1 and MYOM2. The combined carrier frequency of the 8 variants in the previously known LQTS genes was 530 per 100 000 individuals (1:190). p.Tyr315Cys and p.Leu273Phe in KCNQ1 were associated with having a mean QTc interval longer than 500 ms (P=4.2×10-7; odds ratio [OR], 38.6; P=8.4×10-10, OR, 26.5; respectively), and p.Leu273Phe was associated with sudden cardiac death (P=0.0034; OR, 2.99). p.Val215Met in KCNQ1 was carried by 1 in 280 Icelanders, had a smaller effect on the QTc interval (P=1.8×10-44; effect, 22.8 ms), and did not associate with severe clinical events. Conclusions The carrier frequency of associating variants in LQTS genes was higher than previous estimates of the prevalence of LQTS. The variants have variable effects on the QTc interval, and carriers of p.Tyr315Cys and p.Leu273Phe have a more severe disease than carriers of p.Val215Met. These data could lead to improved identification, risk stratification, and a more precise clinical approach to those with QTc prolongation.

Mechanisms underlying phenotypic variation in neurogenetic disorders.

Neurological diseases associated with pathogenic variants in a specific gene, or even with a specific pathogenic variant, can show profound phenotypic variation with regard to symptom presentation, age at onset and disease course. Highlighting examples from a range of neurogenetic disorders, this Review explores emerging mechanisms that are involved in this variability, including environmental, genetic and epigenetic factors that influence the expressivity and penetrance of pathogenic variants. Environmental factors, some of which can potentially be modified to prevent disease, include trauma, stress and metabolic changes. Dynamic patterns of pathogenic variants might explain some of the phenotypic variations, for example, in the case of disorders caused by DNA repeat expansions such as Huntington disease (HD). An important role for modifier genes has also been identified in some neurogenetic disorders, including HD, spinocerebellar ataxia and X-linked dystonia-parkinsonism. In other disorders, such as spastic paraplegia, the basis for most of the phenotypic variability remains unclear. Epigenetic factors have been implicated in disorders such as SGCE-related myoclonus-dystonia and HD. Knowledge of the mechanisms underlying phenotypic variation is already starting to influence management strategies and clinical trials for neurogenetic disorders.

Exome and RNA-Seq analyses of an incomplete penetrance variant in USP9X in female-specific syndromic intellectual disability.

Pathogenic variants in USP9X, on X chromosome, have been implicated in syndromic intellectual disability (ID) in both males and females with distinct craniofacial features. We report a truncating variant, c.885_889delAAAAG, p.(Lys296Serfs*4), in the USP9X gene with incomplete penetrance in two nontwin female siblings with phenotypic resemblance to female-specific syndromic ID (MIM 300969, also known as MRX99F). To investigate the possible genetic etiology of the reduced penetrance, X-inactivation, RNA-Seq, and full quad exome analyses were attempted, but failed to identify a promising candidate modifier. While the penetrance of pathogenic variants in USP9X in female appears to be high (95%) and the variants frequently occur de novo, incomplete penetrance should be considered.

DNA-based screening and personal health: a points to consider statement for individuals and health-care providers from the American College of Medical Genetics and Genomics (ACMG)

DNA-based screening and personal health: a points to consider statement for individuals and health-care providers from the American College of Medical Genetics and Genomics (ACMG)

Prevalence of clinically actionable disease variants in exceptionally long-lived families

BackgroundPhenotypic expression of pathogenic variants in individuals with no family history of inherited disorders remains unclear.MethodsWe evaluated the prevalence of pathogenic variants in 25 genes associated with Mendelian-inherited disorders in 3015 participants from 485 families in the Long Life Family Study (LLFS). Boot-strapping and Fisher’s exact test were used to determine whether allele frequencies in LLFS were significantly different from the allele frequencies reported in publicly available genomic databases.ResultsThe proportions of pathogenic autosomal dominant mutation carriers in BRCA1 and SDHC in LLFS study participants were similar to those reported in publicly available genomic databases (0.03% vs. 0.0008%, p = 1 for BRCA1, and 0.08% vs. 0.003%, p = 0.05 for SDHC). The frequency of carriers of pathogenic autosomal recessive variants in CPT2, ACADM, SUMF1, WRN, ATM, and ACADVL were also similar in LLFS as compared to those reported in genomic databases. The lack of clinical disease among LLFS participants with well-established pathogenic variants in BRCA1 and SDHC suggests that penetrance of pathogenic variants may be different in long lived families.ConclusionFurther research is needed to better understand the penetrance of pathogenic variants before expanding large scale genomic testing to asymptomatic individuals.

Abstract P5-03-02: Cancer risks associated with pathogenic variants in the ataxia telangiectasia mutated (ATM) gene

Abstract Background: Germ-line pathogenic variants (PV) in ATM are often considered low-to-moderate penetrance risk factors for breast cancer (BC), conferring a two-fold increased BC risk among heterozygous PV carriers. Several other cancers have been associated with ATM PV such as melanoma, thyroid cancer, prostate cancer, pancreatic cancer, gastro-esophageal cancers, colorectal cancer, and ovarian cancer. Estimating the diverse cancer risks attributable to ATM PVs may present challenges due to the low-to-moderate penetrance of ATM PV for some cancers, requiring large samples of tested patients to estimate risk with precision, and the potential for substantial variability in penetrance of particular ATM PV such as the c.7271T>G PV reported by previous studies. We investigated cancer risks with ATM PV in a large clinical testing dataset. Methods: Results of 614,344 individuals undergoing clinical analysis of ATM as part of a multi-gene hereditary cancer gene panel between 09/2013 and 06/2019 were reviewed. Patient age, sex, ancestry, personal and family cancer history were extracted from a test requisition form. PV included variants classified as suspected deleterious or deleterious (hereafter referred to as pathogenic). Risk estimates are estimated using multivariate logistic regression and are reported as odds ratios (OR) with 95% confidence intervals (CI). Results: PV in ATM were identified in 4,372/614,344 (0.7%) individuals: 4,155/592,881 (0.7%) females and 217/21,463 (1.0%) males. 1,603/4,155 (38.6%) of female ATM PV carriers had invasive BC or DCIS. Overall, ATM PV were associated with a 2-fold increased risk for invasive BC [OR 2.01, 95% CI 1.86-2.16] and DCIS [OR 1.82, 95% CI 1.62-2.04]. A prevalent missense PV c.7271T>G, predicted to lead to inactivation of ATM kinase activity and that has previously been described as high penetrance (Goldgar DE et al, Breast Cancer Res 2011), represented 5.1% (n=223) of all ATM PV, and was associated with a particularly high risk of invasive BC [OR 3.80, 95% CI 2.78-5.19] but no increased risk of DCIS. Significantly elevated risks of pancreatic cancer, gastric cancer, prostate cancer, ovarian cancer, colon cancer and melanoma were also observed among ATM PV carriers (see Table 1). Median age of invasive BC diagnosis was similar in carriers and non-carriers of ATM PV. Conclusions: ATM PV are associated with 1.5-fold to >4-fold increased cancer risks across a variety of disease sites, including invasive BC (2-fold increased risk). Cancer risks also demonstrate mutation-specific variability, as suggested by the 4-fold increased risk of invasive BC in carriers of the ATM PV c.7271T>G. Larger and/or pooled studies are critical to further refine the breadth and magnitude of ATM-associated cancer risk and to improve clinical management guidelines for ATM PV carriers. Table 1: Odds ratios for cancer risks in c.7271T>G and all other ATM PV carriersAll ATM PVs (excluding c.7271T>G)c.7271T>GCancer OR (95% CI)p-valueOR (95% CI)p-valueBreast, Invasive1.94 (1.79, 2.09)<0.00013.80 (2.78, 5.19)<0.0001Breast, DCIS1.83 (1.62, 2.05)<0.00011.63 (0.97, 2.74)0.0624Breast, Lobular invasive0.94 (0.73, 1.21)0.62330.84 (0.27, 2.64)0.7671Breast, Male1.44 (0.86, 2.42)0.16884.24 (0.46, 39.15)0.2032Ovarian1.55 (1.32, 1.82)<0.00011.99 (0.99, 4.02)0.0532Colorectal1.51 (1.25, 1.82)<0.00011.67 (0.67, 4.18)0.2693Endometrial1.10 (0.88, 1.39)0.39610.89 (0.28, 2.81)0.8401Melanoma1.44 (1.14, 1.81)0.00182.16 (1.00, 4.64)0.0491Prostate2.61 (1.93, 3.52)<0.00014.37 (0.70, 27.26)0.1146Pancreatic4.18 (3.17, 5.49)<0.00012.50 (0.34, 18.21)0.3660Gastric3.09 (1.73, 5.53)0.0001—— Citation Format: Michael J Hall, Katie Larson, Ryan Bernhisel, Elisha Hughes, Eric Rosenthal, Nanda Singh, Johnathan M Lancaster, Allison W Kurian. Cancer risks associated with pathogenic variants in the ataxia telangiectasia mutated (ATM) gene [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-03-02.

Prevalence and penetrance of breast cancer-associated mutations identified by multiple-gene sequencing in the Women’s Health Initiative.

1513 Background: Next-generation sequencing enables rapid analysis of many inherited cancer susceptibility genes. Little is known about the prevalence and penetrance of pathogenic variants (PVs) in such genes among post-menopausal women with breast cancer, who comprise the majority of all breast cancer patients. Methods: The Women’s Health Initiative enrolled post-menopausal women from 1993-1998. We conducted a nested case-control study using banked DNA samples of 2,195 women who subsequently developed invasive breast cancer (cases) and 2,322 cancer-free controls. Sequenced genes were APC, ATM, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A (p16INK4a and p14ARF) , CHEK2, EPCAM, GREM1, MLH1, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, POLD1, POLE, PTEN, RAD51C, RAD51D, SMAD4, STK11, and TP53. PV were defined using American College of Medical Genetics criteria. PV prevalence is reported as proportions and penetrance as the odds ratio (OR) and 95% confidence interval (CI) of PV versus none among cases versus controls. Results: Among cases, the median age at diagnosis was 73 years; 66% were White, 18% Black, 6% Hispanic, 6% Asian and 4% other. The prevalence of PVs in any gene was significantly higher in cases (6.61%, 95% CI 5.57-7.65%) versus controls (4.09%, 95% CI 3.29-4.90%). The prevalence of BRCA1/2 PVs was 1.2% in cases and 0.22% in controls. Among cases, the prevalence of PVs in other breast cancer-risk genes was 2.3% ( ATM, CDH1, BARD1, BRIP1, CHEK2, NBN, and PALB2 collectively), two-fold higher than PVs in BRCA1/2. Prevalence of BRCA1/2 PVs decreased with age among cases, while prevalence of ATM, CHEK2 and PALB2 PVs did not. Statistically significant ORs for breast cancer penetrance were observed for BRCA1 (5.43, 95% CI 1.19-51.52), BRCA2 (4.71, 95% CI 1.84-15.08), BARD1 (9.78, 95% CI 1.04-1295.87) and PALB2 (6.30, 95% CI 1.93-31.94). Conclusions: Approximately 7% of women diagnosed with post-menopausal breast cancer carry a PV in a cancer susceptibility gene. In contrast to studies of younger breast cancer patients, PVs in other breast cancer-related genes were two times more common than in BRCA1/2. Results may guide genetic testing of women with post-menopausal breast cancer.