The prevalence of germ line mutations in non‐BRCA1/2 genes associated with hereditary breast cancer (BC) is low, and the role of some of these genes in BC predisposition and pathogenesis is conflicting. In this study, 5589 consecutive BC index patients negative for pathogenic BRCA1/2 mutations and 2189 female controls were screened for germ line mutations in eight cancer predisposition genes (ATM,CDH1,CHEK2,NBN,PALB2,RAD51C,RAD51D, and TP53). All patients met the inclusion criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for germ line testing. The highest mutation prevalence was observed in the CHEK2 gene (2.5%), followed by ATM (1.5%) and PALB2 (1.2%). The mutation prevalence in each of the remaining genes was 0.3% or lower. Using Exome Aggregation Consortium control data, we confirm significant associations of heterozygous germ line mutations with BC for ATM (OR: 3.63, 95%CI: 2.67–4.94), CDH1 (OR: 17.04, 95%CI: 3.54–82), CHEK2 (OR: 2.93, 95%CI: 2.29–3.75), PALB2 (OR: 9.53, 95%CI: 6.25–14.51), and TP53 (OR: 7.30, 95%CI: 1.22–43.68). NBN germ line mutations were not significantly associated with BC risk (OR:1.39, 95%CI: 0.73–2.64). Due to their low mutation prevalence, the RAD51C and RAD51D genes require further investigation. Compared with control datasets, predicted damaging rare missense variants were significantly more prevalent in CHEK2 and TP53 in BC index patients. Compared with the overall sample, only TP53 mutation carriers show a significantly younger age at first BC diagnosis. We demonstrate a significant association of deleterious variants in the CHEK2,PALB2, and TP53 genes with bilateral BC. Both, ATM and CHEK2, were negatively associated with triple‐negative breast cancer (TNBC) and estrogen receptor (ER)‐negative tumor phenotypes. A particularly high CHEK2 mutation prevalence (5.2%) was observed in patients with human epidermal growth factor receptor 2 (HER2)‐positive tumors.

By identifying novel homozygous or compound heterozygous, deleterious CNVs and mutations in eight individuals from six unrelated families with moderate-to-severe ID, early onset epilepsy and behavioural anomalies, we considerably broaden the mutational and clinical spectrum associated with bi-allelic aberrations in CNTNAP2.

Objectives: Health status is represented by people's subjective assessment of their sense of well-being and ability to perform social roles and has been well accepted as a health indicator of different populations. The aim of this study was to determine health-related quality of life in Slovenian population. Methods: We performed a cross-sectional postal survey in a random stratified sample of 1,000 adult Slovenian inhabitants. The questionnaire consisted of the respondents' demographic data (sex, age, education level, employment status, living environment), self-reported chronic conditions, self-reported use of health services and EQ-5D instrument for measuring quality of life. Results: The response rate was 41% (53.1% men, mean age 51.5 years). Respondents reported most problems in the pain dimension of EQ-5D (59.3%), following by mobility (30.4%), anxiety/depression (30.3%), daily activities (29.8%) and self-care (9.0%). At least one moderate problem was reported by 272 (66.3%) respondents. Independent factors, associated with problems in any EQ-5D dimension were primary and vocational education, older age, high blood pressure, rheumatic diseases, back problems, anxiety/depression, a visit to the emergency department in the past year, and a house visit from a family doctor in the past year. Conclusions: The present study showed that the health-related quality of life of the Slovenian inhabitants is lower than the one found in some other European countries. This finding is surprising and also worrying. Because we cannot find any perceptible reason for this observation, larger and prospective studies are needed to confirm those results and to determine the reasons for that.

BackgroundKleefstra syndrome is characterized by intellectual disability, muscular hypotonia in childhood and typical facial features. It results from either a microdeletion of or a deleterious sequence variant in the gene euchromatic histone-lysine N-methyltransferase 1 (EHMT1) on chromosome 9q34.ResultsWe report on a 3-year-old girl with characteristic symptoms of Kleefstra syndrome. Array comparative genomic hybridization analysis revealed a 145 kilobases duplication spanning exons 2 to 10 of EHMT1. Sequence analysis characterized it as an intragenic tandem duplication leading to a frame shift with a premature stop codon in EHMT1.ConclusionsThis is the first description of an intragenic duplication of EHMT1 resulting in Kleefstra syndrome.

POGZ-related disorders (also known as White-Sutton syndrome) encompass a wide range of neurocognitive abnormalities and other accompanying anomalies. Disease severity varies widely among POGZ patients and studies investigating genotype-phenotype association are scarce. Therefore, our aim was to collect data on previously unreported POGZ patients and perform a large-scale phenotype-genotype comparison from published data. Overall, 117 POGZ patients′ genotype and phenotype data were included in the analysis, including 12 novel patients. A severity scoring system was developed for the comparison. Mild and severe phenotypes were compared with the types and location of the variants and the predicted presence or absence of nonsense-mediated RNA decay (NMD). Missense variants were more often associated with mild phenotypes (p = 0.0421) and truncating variants predicted to escape NMD presented with more severe phenotypes (p < 0.0001). Within this group, variants in the prolin-rich region of the POGZ protein were associated with the most severe phenotypes (p = 0.0004). Our study suggests that gain-of-function or dominant negative effect through escaping NMD and the location of the variants in the prolin-rich domain of the protein may play an important role in the severity of manifestations of POGZ–associated neurodevelopmental disorders.