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Steroid hormone receptors are ligand-binding transcription factors essential for mammalian physiology. The androgen receptor (AR) binds androgens mediating gene expression for sexual, somatic, and behavioral functions, and is involved in various conditions including androgen-insensitivity-syndrome (AIS) or prostate cancer. Here we identified functional AIS-patient mutations in the formin and actin nucleator DAAM2. DAAM2 localized to the nucleus and colocalized with the AR to form actin-dependent transcriptional droplets in response to dihydrotestosterone. DAAM2-AR-droplets ranged from 0.02 to 0.06 µm3 in size and associated with active RNA polymerase II. DAAM2 polymerizes actin directly at the AR to promote droplet fusion in a highly dynamic manner and actin polymerization is required for prostate-specific antigen expression in cancer cells. Our data uncover signal-regulated nuclear actin assembly at a steroid hormone receptor necessary for transcription.

The objective of our study was to investigate the impact of the mitochondrial polygenic score (MGS) and lifestyle/environmental data on age at onset in LRRK2 p.Gly2019Ser parkinsonism (LRRK2-PD) and idiopathic Parkinson’s disease (iPD).In this study, we included N=486 patients withLRRK2-PD and N=9259 patients with iPD from AMP-PD, Fox Insight, and a Tunisian Arab-Berber founder population. Genotyping data was utilized to perform the MGS analysis, using 14 Single Nucleotide Polymorphisms (SNPs) from genes causally associated with mitochondrial function and PD risk. Additionally, lifestyle and environmental data were obtained from the PD risk factor questionnaire (PD-RFQ). Correlation analyses and linear regression models were used to assess the relationship between MGS, lifestyle/environment, and AAO.We observed that higher MGS was associated with earlier AAO in patients withLRRK2-PD (p=4.0×10−4, β=-0.18) but not in patients with iPD. A correlation between MGS and AAO was visibly stronger in European ancestryLRRK2-PD patients (p=0.01, r=-0.16) than in Tunisian Arab-Berber patients (p=0.44, r=-0.05). We found that the MGS interacted with coffee (p=0.03, β=-0.38) and caffeinated soda consumption (p=0.03, β=-0.37) inLRRK2-PD and with caffeine soda consumption (p=0.047, β=-0.22) and pesticide exposure (p=0.02, β=-0.37) in iPD. Thus, patients with a high MGS had an earlier AAO only if they consumed caffeine or were exposed to pesticides.The MGS related to mitochondrial function was associated with AAO inLRRK2-PD but not iPD with an ethnic-specific effect. Caffeine consumption or pesticide exposure interacted with MGS to predict PD AAO. Our study suggests gene-environment interactions as modifiers of AAO inLRRK2-PD.

The recent characterization of a group of non-MYC rearranged aggressive B-cell lymphomas, resembling Burkitt lymphoma (BL), characteristically harboring a telomeric 11q loss or combined 11q proximal gains/loss pattern has led to the introduction of the provisional entity of Burkitt-like lymphoma with 11q aberration (BLL-11q). Prompted by the discovery of a telomeric 11q loss in an HIV+ high-grade B-cell lymphoma patient, we investigated an extended cohort of aggressive B-cell lymphomas, enriched for cases with histopathological features intermediate between DLBCL and BL, including double- and triple-hit lymphomas (n = 47), for 11q loss/combined 11q proximal gains/loss pattern by fluorescence in situ hybridization. We provide first evidence that 11q aberrations can be found in both BLL in the context of an underlying HIV infection as well as in high-grade B-cell lymphomas with MYC, BCL2, and/or BCL6 rearrangements. We therefore propose that the clinicopathological spectrum of malignancies carrying this aberration may be broader than previously assumed.

Inflammatory bowel disease (IBD) is often described as a model for modern civilization diseases in which environmental factors trigger disease manifestation in genetically compromised individuals. Little is known about the evolutionary history of variants associated with IBD in modern Europeans. Here, we analysed 610 IBD-variants in 2445 ancient datasets from human remains spanning the last 12,000 years, including genotypes generated from 172 newly collected individuals from the European Neolithic. We found statistically significant differences in the frequencies of 97 IBD variants between Neolithic and modern populations that can be explained by the adoption of an agricultural lifestyle and behaviour and concomitant possible microbiome changes in the earliest farmers. Later admixture events and selection against pathogens largely influenced the genetic risk architecture of IBD in contemporary Europeans. A better understanding of the evolutionary history of disease variants is an important first step in translating genetic findings into preventive health care.

Despite enormous research efforts, the genetic component of longevity has remained largely elusive. The investigation of common variants, mainly located in intronic or regulatory regions, has yielded only little new information on the heritability of the phenotype. Here, we performed a chip-based exome-wide association study investigating 62 488 common and rare coding variants in 1248 German long-lived individuals, including 599 centenarians and 6941 younger controls (age < 60 years). In a single-variant analysis, we observed an exome-wide significant association between rs1046896 in the gene fructosamine-3-kinase-related-protein (FN3KRP) and longevity. Noteworthy, we found the longevity allele C of rs1046896 to be associated with an increased FN3KRP expression in whole blood; a database look-up confirmed this effect for various other human tissues. A gene-based analysis, in which potential cumulative effects of common and rare variants were considered, yielded the gene phosphoglycolate phosphatase (PGP) as another potential longevity gene, though no single variant in PGP reached the discovery p-value (1 × 10E−04). Furthermore, we validated the previously reported longevity locus cyclin-dependent kinase inhibitor 2B antisense RNA 1 (CDKN2B-AS1). Replication of our results in a French longevity cohort was only successful for rs1063192 in CDKN2B-AS1. In conclusion, we identified 2 new potential candidate longevity genes, FN3KRP and PGP which may influence the phenotype through their role in metabolic processes, that is, the reverse glycation of proteins (FN3KRP) and the control of glycerol-3-phosphate levels (PGP).

BackgroundWe describe two unrelated patients who display similar clinical features including telangiectasia, ectodermal dysplasia, brachydactyly and congenital heart disease.MethodsWe performed trio whole exome sequencing and functional analysis using in vitro kinase assays with recombinant proteins.ResultsWe identified two different de novo mutations in protein kinase D1 (PRKD1, NM_002742.2): c.1774G>C, p.(Gly592Arg) and c.1808G>A, p.(Arg603His), one in each patient. PRKD1 (PKD1, HGNC:9407) encodes a kinase that is a member of the protein kinase D (PKD) family of serine/threonine protein kinases involved in diverse cellular processes such as cell differentiation and proliferation and cell migration as well as vesicle transport and angiogenesis. Functional analysis using in vitro kinase assays with recombinant proteins showed that the mutation c.1808G>A, p.(Arg603His) represents a gain-of-function mutation encoding an enzyme with a constitutive, lipid-independent catalytic activity. The mutation c.1774G>C, p.(Gly592Arg) in contrast shows a defect in substrate phosphorylation representing a loss-of-function mutation.ConclusionThe present cases represent a syndrome, which associates symptoms from several different organ systems: skin, teeth, bones and heart, caused by heterozygous de novo mutations in PRKD1 and expands the clinical spectrum of PRKD1 mutations, which have hitherto been linked to syndromic congenital heart disease and limb abnormalities.

Background: Hamartomas of the breast are rare benign tumors. Pre- and also postoperative differentiation from other benign or even malignant tumors is challenging. Case Presentation: A 36-year-old female presented with a giant tumor of the left breast. The patient had suffered from an early breast cancer of the contralateral right breast the year before, which was treated with breast-conserving therapy, radiation, and endocrine therapy ever since. The hamartoma was classified as BI-RADS 2 in mammography and BI-RADS 4 in ultrasound. On clinical examination, a tumor of nearly 15 cm in size led to an abstruse deformity of the breast and the nipple-areola complex. We found an indolent, grand bulging tumor with an elastic texture directly beneath the skin. A biopsy that had been performed before was compatible with the suspected hamartoma. Because of the remaining diagnostic uncertainties after contralateral breast cancer and the progressive malformation of the left breast, a tumor extirpation utilizing a reduction mammaplasty was performed without complications. Subsequent genetic analyses excluded a loss of PTEN in this patient. Conclusion: We presented the rare case of a 36-year-old woman with a history of breast cancer and a 700-g breast hamartoma. The preoperative and even the postoperative specification of a hamartoma remains challenging, and associations with genetic alterations should be considered.

The inclusion of ancestrally diverse participants in genetic studies can lead to new discoveries and is important to ensure equitable health care benefit from research advances. Here, members of the Ethical, Legal, Social, Implications (ELSI) committee of the International Genetic Epidemiology Society (IGES) offer perspectives on methods and analysis tools for the conduct of inclusive genetic epidemiology research, with a focus on admixed and ancestrally diverse populations in support of reproducible research practices. We emphasize the importance of distinguishing socially defined population categorizations from genetic ancestry in the design, analysis, reporting, and interpretation of genetic epidemiology research findings. Finally, we discuss the current state of genomic resources used in genetic association studies, functional interpretation, and clinical and public health translation of genomic findings with respect to diverse populations.

Objective: Brain edema is a common co-manifestation in intracranial meningiomas (IMs). Many studies have been published investigating the pathogeneses of brain edema (BE) and many various factors involved in the development of BE in patients with IMs. However, there are known very few information about [for full text, please go to the a.m. URL]

Measurement of atrial volumes by MRI is becoming increasingly important in pediatric cardiac disorders. However, MRI normal values for atrial volumes in children are lacking.To establish pediatric reference values for atrial volumes.Retrospective.A total of 155 healthy children from two large institutions (103 male, age 13.9 ± 2.8 years, range 4-18 years).A 1.5 T; balanced steady-state free precession (bSSFP) sequence.The monoplane and biplane area-length methods were used to measure minimal and maximal left and right atrial volumes (LADescriptive statistics, lambda-mu-sigma (LMS)-method of Cole and Green, univariable and multivariable linear regression models. A P value 0.05 was considered to be statistically significant.In the multivariable linear model, body surface area was significantly associated with all atrial volumes and sex was significantly associated with RA volumes, LA volumes measured in the 2ch-view as well as biplane LAPediatric MRI reference values for atrial volumes have been provided.2 EVIDENCE LEVEL: 4.

Background: The outcome of cochlear implantation has improved over the last decades, but there are still patients with less benefit. Despite numerous studies examining the cochlear implant (CI) outcome, variations in speech comprehension with CI remains incompletely explained. The aim of this study was therefore to examine preoperative pure-tone audiogram and speech comprehension as well as aetiology, to investigate their relationship with postoperative speech comprehension in CI recipients. Methods: A retrospective study with 664 ears of 530 adult patients was conducted. Correlations between the target variable postoperative word comprehension with the preoperative speech and sound comprehension as well as aetiology were investigated. Significant correlations were inserted into multivariate models. Speech comprehension measured as word recognition score at 70 dB with CI was analyzed as (i) a continuous and (ii) a dichotomous variable. Results: All variables that tested preoperative hearing were significantly correlated with the dichotomous target; with the continuous target, all except word comprehension at 65 dB with hearing aid. The strongest correlation with postoperative speech comprehension was seen for monosyllabic words with hearing aid at 80 dB. The preoperative maximum word comprehension was reached or surpassed by 97.3% of CI patients. Meningitis and congenital diseases were strongly negatively associated with postoperative word comprehension. The multivariate model was able to explain 40% of postoperative variability. Conclusion: Speech comprehension with hearing aid at 80 dB can be used as a supplementary preoperative indicator of CI-aided speech comprehension and should be measured regularly in the clinical routine. Combining audiological and aetiological variables provides more insights into the variability of the CI outcome, allowing for better patient counselling.