Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Diagnostic Analyses of Retinal Dystrophy Genes: Current Status and Perspective

Over the past decade, novel high-throughput DNA sequencing technologies have revolutionised both research and diagnostic testing for monogenic disorders. This applies particularly to genetically very heterogeneous disorders like retinal dystrophies (RDs). Next-generation sequencing (NGS) today is considered as reliable as Sanger sequencing, which had been the gold standard for decades. Today, comprehensive NGS-based diagnostic testing reveals the causative mutations in the majority of RD patients, with important implications for genetic counselling for recurrence risks and personalised medical management (from interdisciplinary surveillance to prophylactic measures and, albeit yet rare, [gene] therapy). While DNA sequencing is - in most cases - no longer the diagnostic bottleneck, one needs to be aware of interpretation pitfalls and dead ends. The advent of new (NGS) technologies will solve some of these issues. However, specialised medical geneticists who are familiar with the peculiarities of certain RD genes and closely interact with ophthalmologists will remain key to successful RD research and diagnostic testing for the benefit of the patients. This review sheds light on the current state of the field, its challenges and potential solutions

Despite Challenges and Pitfalls: How Ophthalmology Benefits from the Use of Next-Generation Sequencing

Within a few years, high-throughput sequencing (next-generation sequencing, NGS) has become a routine method in genetic diagnostics and has largely replaced conventional Sanger sequencing. The complexity of NGS data requires sound bioinformatic analysis: pinpointing the disease-causing variants may be difficult, and erroneous interpretations must be avoided. When looking at the group of retinal dystrophies as an example of eye disorders with extensive genetic heterogeneity, one can clearly say that NGS-based diagnostics yield important information for most patients and physicians, and that it has furthered our knowledge significantly. Furthermore, NGS has accelerated ophthalmogenetic research aimed at the identification of novel eye disease genes

The Bardet-Biedl Syndrome - Diagnosis and Follow-up

The Bardet-Biedl syndrome (BBS) is a rare inherited ciliopathy, which is accompanied by retinal disease, i.e. rod-cone dystrophy ( retinitis pigmentosa, RP) and other symptoms, especially truncal obesity, polydactyly, renal abnormalities as well as reduced intelligence or learning difficulties. 25 BBS genes are currently known, and these are responsible for the structure and function of primary cilia. Because ciliary integrity is crucial for numerous pathways of developmental signaling, their dysfunction may cause multisystemic disorders - like BBS. Physicians benefit greatly from new molecular genetic methods that have made genetically heterogeneous conditions diagnostically accessible: By next-generation sequencing (NGS), all BBS-associated genes can be analysed simultaneously in a gene panel. As regards the retinal phenotype, genotype-phenotype correlations are not significant. Besides classical autosomal recessive inheritance, oligogenic/triallelic traits have been reported, but these seem to play a minor role, if any (as a growing number of large-scale NGS-based studies suggests). In the absence of causal therapy, the mainstay of ophthalmological endeavour is focused on visual rehabilitation with low vision aids, use of the white cane and training to develop everyday life skills

The supposed tumor suppressor gene WWOX is mutated in an early lethal microcephaly syndrome with epilepsy, growth retardation and retinal degeneration

Background: WWOX, encoding WW domain-containing oxidoreductase, spans FRA16D, the second most common chromosomal fragile site frequently altered in cancers. It is therefore considered a tumor suppressor gene, but its direct implication in cancerogenesis remains controversial. Methods and results: By whole-exome sequencing, we identified a homozygous WWOX nonsense mutation, p.Arg54*, in a girl from a consanguineous family with a severe syndrome of growth retardation, microcephaly, epileptic seizures, retinopathy and early death, a phenotype highly similar to the abormalities reported in lde/lde rats with a spontaneous functional null mutation of Wwox. As in rats, no tumors were observed in the patient or heterozygous mutation carriers. Conclusions: Our finding, a homozygous loss-of-function germline mutation in WWOX in a patient with a lethal autosomal recessive syndrome, supports an alternative role of WWOX and indicates its importance for human viability

OTUD6B-associated intellectual disability: novel variants and genetic exclusion of retinal degeneration as part of a refined phenotype

Biallelic pathogenic variants of OTUD6B have recently been described to cause intellectual disability (ID) with seizures. Here, we report the clinical and molecular characterization of five additional patients (from two unrelated Egyptian families) with ID due to homozygous OTUD6B variants. In Family I, the two affected brothers had additional retinal degeneration, a symptom not yet reported in OTUD6B-related ID. Whole-exome sequencing (WES) identified a novel nonsense variant in OTUD6B (c.271C>T, p.(Gln91Ter)), but also a nonsense variant in RP1L1 (c.5959C>T, p.(Gln1987Ter)), all in homozygous state. Biallelic pathogenic variants in RP1L1 cause autosomal recessive retinitis pigmentosa type 88 (RP88). Thus, RP1L1 dysfunction likely accounts for the visual phenotype in this family with two simultaneous autosomal recessive disorders. In Family II, targeted sequencing revealed a novel homozygous missense variant (c.767G>T, p.(Gly256Val)), confirming the clinically suspected OTUD6B-related ID. Consistent with the clinical variability in previously reported OTUD6B patients, our patients showed inter- and intrafamilial differences with regard to the clinical and brain imaging findings. Interestingly, various orodental features were present including macrodontia, dental crowding, abnormally shaped teeth, and thick alveolar ridges. Broad distal phalanges (especially the thumbs and halluces) with prominent interphalangeal joints and fetal pads were recognized in all patients and hence considered pathognomonic. Our study extends the spectrum of the OTUD6B-associated phenotype. Retinal degeneration, albeit present in both patients from Family I, was shown to be unrelated to OTUD6B, demonstrating the need for in-depth analysis of WES data in consanguineous families to uncover simultaneous autosomal recessive disorders