Search

Summary: Background: The developmental and epileptic encephalopathies (DEEs) are the most severe group of epilepsies which co-present with developmental delay and intellectual disability (ID). DEEs usually occur in people without a family history of epilepsy and have emerged as primarily monogenic, with damaging rare mutations found in 50% of patients. Little is known about the genetic architecture of patients with DEEs in whom no pathogenic variant is identified. Polygenic risk scoring (PRS) is a method that measures a person's common genetic burden for a trait or condition. Here, we used PRS to test whether genetic burden for epilepsy is relevant in individuals with DEEs, and other forms of epilepsy with ID. Methods: Genetic data on 2,759 cases with DEEs, or epilepsy with ID presumed to have a monogenic basis, and 447,760 population-matched controls were analysed. We compared PRS for ‘all epilepsy’, ‘focal epilepsy’, and ‘genetic generalised epilepsy’ (GGE) between cases and controls. We performed pairwise comparisons between cases stratified for identifiable rare deleterious genetic variants and controls. Findings: Cases of presumed monogenic severe epilepsy had an increased PRS for ‘all epilepsy’ (p

Although the increase in risk of developing breast, ovarian, and prostate cancer in BRCA1 and BRCA2 mutation carriers has been studied extensively, its impact on mortality is not well quantified. Further, possible effect of BRCA mutations on non-cancer mortality risk has not been examined.Using mortality data from the relatives of 5,287 genotyped participants, of whom 120 carried a BRCA Ashkenazi Jewish founder mutation, in a community-based study of the Ashkenazi Jewish population in the Washington D.C area, we examined the association between the three Ashkenazi BRCA founder mutations and risk of overall and non-cancer mortality. To examine risks beyond the established effects of these mutations, we analyzed the data excluding both deaths and follow-up times after reported diagnosis of melanoma and cancer of the breast, ovary, prostate, and pancreas. Using an extension of the kin-cohort method that accounts for informative censoring, we estimated that, in the absence of breast, ovarian, and pancreatic cancers, and melanoma, female carriers had a life expectancy that was 6.8 years lower (95% CI: 1.2-10.5) than non-carriers. In male mutation carriers, the reduction in life expectancy, in the absence of prostate and pancreatic cancers and melanoma, was 3.7 (95% CI: -0.4, 6.8) years. When deaths and follow-up times after any cancer diagnosis were excluded, the difference in life expectancy was 5.7 years for women (95% CI: -0.1, 10.4) and 3.7 years for men (95% CI: -0.4, 6.9). An overall test of association for men and women together showed a statistically significant association between BRCA1/2 mutations and increased non-cancer mortality (p = 0.024).These findings suggest that there may be unknown effects of BRCA1/2 mutations on non-neoplastic diseases that cause death at older ages.

Background: Polymorphisms within the MTHFD1L gene were previously associated with risk of neural tube defects in Ireland. We sought to test the most significant MTHFD1L polymorphisms for an association with risk of cleft in an Irish cohort. This required the development of a new melting curve assay to genotype the technically challenging MTHFD1L triallelic deletion/insertion polymorphism (rs3832406). Methods: Melting curve analysis was used to genotype the MTHFD1L triallelic deletion/insertion polymorphism (rs3832406) and a Single Nucleotide Polymorphism rs17080476 in an Irish cohort consisting of 981 Irish case-parent trios and 1,008 controls. Tests for association with nonsyndromic cleft lip with or without cleft palate and cleft palate included case/control analysis, mother/control analysis and Transmission Disequilibrium Tests of case-parent trios. Results: A successful melting curve genotyping assay was developed for the deletion/insertion polymorphism (rs3832406). The TDT analysis initially showed that the rs3832406 polymorphism was associated with isolated cleft lip with or without cleft palate. However, corrected p-values indicated that this association was not significant. Conclusions: Melting Curve Analysis can be employed to successfully genotype challenging polymorphisms such as the MTHFD1L triallelic deletion/insertion polymorphism (DIP) reported here (rs3832406) and is a viable alternative to capillary electrophoresis. Corrected p-values indicate no association between MTHFD1L and risk of cleft in an Irish cohort. [ABSTRACT FROM AUTHOR]