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Nazneen Rahman and colleagues show that germline inactivating mutations in RAD51D confer susceptibility to ovarian cancer. They further show that RAD51D-deficient cells are sensitive to PARP inhibition, suggesting a possible strategy for treating cancers arising in RAD51D mutation carriers. Recently, RAD51C mutations were identified in families with breast and ovarian cancer 1 . This observation prompted us to investigate the role of RAD51D in cancer susceptibility. We identified eight inactivating RAD51D mutations in unrelated individuals from 911 breast-ovarian cancer families compared with one inactivating mutation identified in 1,060 controls ( P = 0.01). The association found here was principally with ovarian cancer, with three mutations identified in the 59 pedigrees with three or more individuals with ovarian cancer ( P = 0.0005). The relative risk of ovarian cancer for RAD51D mutation carriers was estimated to be 6.30 (95% CI 2.86–13.85, P = 4.8 × 10 −6 ). By contrast, we estimated the relative risk of breast cancer to be 1.32 (95% CI 0.59–2.96, P = 0.50). These data indicate that RAD51D mutation testing may have clinical utility in individuals with ovarian cancer and their families. Moreover, we show that cells deficient in RAD51D are sensitive to treatment with a PARP inhibitor, suggesting a possible therapeutic approach for cancers arising in RAD51D mutation carriers.

Background Carriers of germline pathogenic variants (PVs) in the BRCA1 and BRCA2 genes are at higher risk of developing breast and ovarian cancer than the general population. It is unclear if these PVs influence other breast or ovarian cancer risk factors, including age at menopause (ANM), age at menarche (AAM), menstrual cycle length, BMI or height. There is a biological rationale for associations between BRCA1 and BRCA2 PVs and reproductive traits, for example involving DNA damage and repair mechanisms. The evidence for or against such associations is limited. Methods We used data on 3,046 BRCA1 and 3,264 BRCA2 PV carriers, and 2,857 non-carrier female relatives of PV carriers from the Epidemiological Study of Familial Breast Cancer (EMBRACE). Associations between ANM and PV carrier status was evaluated using linear regression models allowing for censoring. AAM, menstrual cycle length, BMI, and height in carriers and non-carriers were compared using linear and multinomial logistic regression. Analyses were adjusted for potential confounders, and weighted analyses carried out to account for non-random sampling with respect to cancer status. Results No statistically significant difference in ANM between carriers and non-carriers was observed in analyses accounting for censoring. Linear regression effect sizes for ANM were -0.002 (95%CI: -0.401, 0.397) and -0.172 (95%CI: -0.531, 0.188), for BRCA1 and BRCA2 PV carriers respectively, compared with non-carrier women. The distributions of AAM, menstrual cycle length and BMI were similar between PV carriers and non-carriers, but BRCA1 PV carriers were slightly taller on average than non-carriers (0.5 cm difference, p  = 0.003). Conclusion Information on the distribution of cancer risk factors in PV carriers is needed for incorporating these factors into multifactorial cancer risk prediction algorithms. Contrary to previous reports, we found no evidence that BRCA1 or BRCA2 PV are associated with hormonal or anthropometric factors, except for a weak association with height. We highlight methodological considerations and data limitations inherent in studies aiming to address this question.

Establishing a universally applicable protocol to assess the impact of BRCA1 variants of uncertain significance (VUS) expression is a problem which has yet to be resolved despite major progresses have been made. The numerous difficulties which must be overcome include the choices of cellular models and functional assays. We hypothesised that the use of induced pluripotent stem (iPS) cells might facilitate the standardisation of protocols for classification, and could better model the disease process. We generated eight iPS cell lines from patient samples expressing either BRCA1 pathogenic variants, non-pathogenic variants, or BRCA1 VUSs. The impact of these variants on DNA damage repair was examined using a ɣH2AX foci formation assay, a Homologous Repair (HR) reporter assay, and a chromosome abnormality assay. Finally, all lines were tested for their ability to differentiate into mammary lineages in vitro. While the results obtained from the two BRCA1 pathogenic variants were consistent with published data, some other variants exhibited differences. The most striking of these was the BRCA1 variant Y856H (classified as benign), which was unexpectedly found to present a faulty HR repair pathway, a finding linked to the presence of an additional variant in the ATM gene. Finally, all lines were able to differentiate first into mammospheres, and then into more advanced mammary lineages expressing luminal- or basal-specific markers. This study stresses that BRCA1 genetic analysis alone is insufficient to establish a reliable and functional classification for assessment of clinical risk, and that it cannot be performed without considering the other genetic aberrations which may be present in patients. The study also provides promising opportunities for elucidating the physiopathology and clinical evolution of breast cancer, by using iPS cells.

ObjectivesThis study aimed to explore the experiences of parents caring for children with intellectual and developmental disabilities (IDD) during the UK national lockdown in spring 2020, resulting from the COVID-19 pandemic.DesignParticipants were identified using opportunity sampling from the IMAGINE-ID national (UK) cohort and completed an online survey followed by a semistructured interview. Interviews were analysed using thematic analysis.SettingInterviews were conducted over the telephone in July 2020 as the first UK lockdown was ending.Participants23 mothers of children with intellectual and developmental disabilities aged 5–15 years were recruited.ResultsThemes reported by parents included: managing pre-existing challenges during a time of extreme change, having mixed emotions about the benefits and difficulties that arose during the lockdown and the need for appropriate, individualised support.ConclusionsOur findings confirm observations previously found in UK parents of children with IDD and provide new insights on the use of technology during the pandemic for schooling and healthcare, as well as the need for regular check-ins.

Lynch syndrome (LS) is an inherited predisposition to early onset of various cancers, caused by mutation in a DNA mismatch repair (MMR) gene. In heterozygous MMR+/− carriers, somatic mutation, loss or silencing of the wild type allele increases the mutation rate, facilitating the initiation of MMR-defective cancers. These cancers are characterized by instability at short tandem repeats (STRs) and in telomeric DNA. We have investigated telomere length in saliva DNA from LS and control families, using single telomere analysis at XpYp and 12q and by qPCR to measure total telomeric DNA. Single telomere analysis showed a trend for shorter XpYp telomeres in MSH2+/− carriers compared to MLH1+/− carriers or controls, but this was masked in the comparative analysis of total telomeric DNA. Comparison of age-adjusted telomere length within families showed that neither MSH2+/− or MLH1+/− children had consistently shorter or longer telomeres than their MMR+/− parent, indicating the absence of an inter-generational effect on telomere length. Unexpectedly however, wildtype children in families with MSH2 mutations, had significantly longer XpYp telomeres than their MMR+/− parent. Altogether our data suggest that MMR insufficiency, particularly in MSH2+/− carriers, increases telomere instability and somatic cell turnover during the lifetime of LS mutation carriers but has minimal consequences for telomere length in the germline.

In January 2019, a new nationally commissioned Genomic Medicine Service (GMS) has now commenced in the NHS. Capitalising on the infrastructure developed through the 100,000 Genomes Project, the GMS is underpinned by seven supra-regional Genomic Laboratory Hubs (GLHs) delivering the new inherited rare disease and cancer somatic tissue genetic test directory. This replaces the UKGTN test directory, with the aim of standardising criteria for whole genome sequencing or targeted panel tests where applicable. The new test directory will define who can order specific genetic tests under prescribed eligibility criteria. In keeping with Dame Sally Davies' white paper Generation Genome, this will further democratise genetic testing and, in some situations, avoid the need to refer to clinical genetics to access testing. The aim is to simplify patient pathways and reduce regional or social inequalities. We will discuss the implications of whole genome sequencing and the potential impact of the new nationally commissioned GMS for both patients, their relatives and clinicians. We will also discuss the imminent challenges in implementing genomic medicine into the NHS, and the future impact of novel technologies on service delivery as genomic medicine becomes increasingly integrated into routine healthcare.

Ethnic disparities in use of cancer genetics services raise concerns about equitable opportunity to benefit from familial cancer risk assessment, improved survival and quality of life. This paper considers available research to explore what may hinder or facilitate minority ethnic access to cancer genetics services. We sought to inform service development for people of South Asian, African or Irish origin at risk of familial breast, ovarian, colorectal and prostate cancers in the UK. Relevant studies from the UK, North America and Australasia were identified from six electronic research databases. Current evidence is limited but suggests low awareness and understanding of familial cancer risk among minority ethnic communities studied. Socio-cultural variations in beliefs, notably stigma about cancer or inherited risk of cancer, are identified. These factors may affect seeking of advice from providers and disparities in referral. Achieving effective cross-cultural communication in the complex contexts of both cancer and genetics counselling, whether between individuals and providers, when mediated by third party interpreters, or within families, pose further challenges. Some promising experience of facilitating minority ethnic access has been gained by introduction of culturally sensitive provider and counselling initiatives, and by enabling patient self-referral. However, further research to inform and assess these interventions, and others that address the range of challenges identified for cancer genetics services are needed. This should be based on a more comprehensive understanding of what happens at differing points of access and interaction at community, cancer care and genetic service levels.

Purpose Diagnosis of genetic disorders is hampered by large numbers of variants of uncertain significance (VUSs) identified through next-generation sequencing. Many such variants may disrupt normal RNA splicing. We examined effects on splicing of a large cohort of clinically identified variants and compared performance of bioinformatic splicing prediction tools commonly used in diagnostic laboratories. Methods Two hundred fifty-seven variants (coding and noncoding) were referred for analysis across three laboratories. Blood RNA samples underwent targeted reverse transcription polymerase chain reaction (RT-PCR) analysis with Sanger sequencing of PCR products and agarose gel electrophoresis. Seventeen samples also underwent transcriptome-wide RNA sequencing with targeted splicing analysis based on Sashimi plot visualization. Bioinformatic splicing predictions were obtained using Alamut, HSF 3.1, and SpliceAI software. Results Eighty-five variants (33%) were associated with abnormal splicing. The most frequent abnormality was upstream exon skipping (39/85 variants), which was most often associated with splice donor region variants. SpliceAI had greatest accuracy in predicting splicing abnormalities (0.91) and outperformed other tools in sensitivity and specificity. Conclusion Splicing analysis of blood RNA identifies diagnostically important splicing abnormalities and clarifies functional effects of a significant proportion of VUSs. Bioinformatic predictions are improving but still make significant errors. RNA analysis should therefore be routinely considered in genetic disease diagnostics.

BackgroundCowden's syndrome is a rare, autosomal dominant disease caused by mutations in the phosphoinositide 3-kinase and phosphatase and tensin homolog (PTEN) gene. It is associated with hamartomatous polyposis of the gastrointestinal tract, mucocutaneous lesions and increased risk of developing certain types of cancer. In addition to increased risk of tumour development, mutations in PTEN have also been associated with autoimmunity in both mice and humans. Until now, however, an association between Cowden's syndrome and immune deficiency has been reported in a single patient only.Methods and resultsTwo patients with Cowden's syndrome and an increased frequency of infections were investigated for possible underlying immunodeficiency. In one patient, hypogammaglobulinaemia with a functional antibody deficiency was identified, while the other patient had a persisting CD4+ T cell lymphopenia (with normal antibody production).ConclusionsOur data indicate that Cowden's syndrome may be associated with both T cell and B cell immune dysfunction. We recommend that patients with Cowden's syndrome and an increased frequency of infections are investigated for associated immunodeficiency.