Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.

BACKGROUND: Genetic testing for breast cancer susceptibility is widely used, but for many genes, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are lacking. METHODS: We used a panel of 34 putative susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 controls. In separate analyses for protein-truncating variants and rare missense variants in these genes, we estimated odds ratios for breast cancer overall and tumor subtypes. We evaluated missense-variant associations according to domain and classification of pathogenicity. RESULTS: Protein-truncating variants in 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2) were associated with a risk of breast cancer overall with a P value of less than 0.0001. Protein-truncating variants in 4 other genes (BARD1, RAD51C, RAD51D, and TP53) were associated with a risk of breast cancer overall with a P value of less than 0.05 and a Bayesian false-discovery probability of less than 0.05. For protein-truncating variants in 19 of the remaining 25 genes, the upper limit of the 95% confidence interval of the odds ratio for breast cancer overall was less than 2.0. For protein-truncating variants in ATM and CHEK2, odds ratios were higher for estrogen receptor (ER)-positive disease than for ER-negative disease; for protein-truncating variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D, odds ratios were higher for ER-negative disease than for ER-positive disease. Rare missense variants (in aggregate) in ATM, CHEK2, and TP53 were associated with a risk of breast cancer overall with a P value of less than 0.001. For BRCA1, BRCA2, and TP53, missense variants (in aggregate) that would be classified as pathogenic according to standard criteria were associated with a risk of breast cancer overall, with the risk being similar to that of protein-truncating variants. CONCLUSIONS: The results of this study define the genes that are most clinically useful for inclusion on panels for the prediction of breast cancer risk, as well as provide estimates of the risks associated with protein-truncating variants, to guide genetic counseling. (Funded by European Union Horizon 2020 programs and others.).

Impact of post-COVID-19 olfactory disorders on quality of life, hedonic experiences and psychiatric dimensions in general population.

BACKGROUND AND OBJECTIVE: Olfactory disorders in COVID-19 impact quality of life and may lead to psychological impairments. Prevalence ranges from 8 to 85%, persisting in about 30% of cases. This study aimed to evaluate the 6-month post-COVID-19 impact on quality of life, hedonic experiences, anxiety and depression due to olfactory disorders. Additionally, it sought to compare psychophysical tests and self-perceived olfactory evaluations. METHODS: A prospective, longitudinal study was conducted over baseline (T0) and 6 months (T1) on individuals with persistent olfactory disorders post-COVID-19 for more than 6 weeks. Psychophysical tests employed the Sniffin' Sticks Test® (TDI score), and self-perceived olfactory evaluation used a Visual Analogue Scale. Quality of life was assessed with an Olfactive Disorder Questionnaire and the French version of the Quality of Life and Diet Questionnaire. Hedonic experiences were gauged using the Snaith-Hamilton Pleasure Scale, while anxiety and depression dimensions were measured by The State-Trait Anxiety Inventory, The Post Traumatic Stress Checklist Scale, and Hamilton Rating Scale for Depression. Participants were classified into the "normosmic group" (NG) and the "olfactory disorders group" (ODG) at T0 and T1 based on the TDI score. RESULTS: Were included 56 participants (58.93% women, 41.07% men) with a mean age of 39.04 years and a mean duration of post-COVID-19 olfactory disorders of 5.32 months. At T1, ODG had a significantly lower quality of life and hedonic experiences than NG. No significant differences in anxiety and depression dimensions were observed between groups. At T0, psychophysical tests and self-perceived olfactory evaluations were significantly correlated with quality of life and hedonic experiences in both groups. At T1, self-perceived olfactory evaluation in NG correlated significantly with quality of life, hedonic experiences, anxiety and depression dimensions, whereas ODG only correlated with hedonic experiences. CONCLUSION: Individuals with persistent post-COVID-19 olfactory disorders after six months demonstrated compromised quality of life and hedonic experiences. Self-perceived olfactory evaluation played a more significant role in influencing quality of life and the dimension of anxiety and depression than the psychophysical presence of olfactory disorders. These findings emphasize the importance of considering patients' perceptions to comprehensively assess the impact of olfactory disorders on their well-being. TRIAL REGISTRATION: ClinicalTrials.gov number (ID: NCT04799977).

Psychosocial and emotional management of work experience in palliative care nurses: A qualitative exploration.

BACKGROUND: Palliative care, a crucial aspect of healthcare, faces challenges in psychosocial and emotional management among nurses. With an increasing need for palliative services globally, addressing the emotional well-being of nurses becomes pivotal. AIM: To explore nurses' psychosocial and emotional work experiences in a palliative care department. The focus is on understanding the challenges, identifying coping strategies, and assessing the impact on professional and private life when facing those experiences. METHODS: A phenomenologic-hermeneutical study involving semi-structured interviews was conducted to comprehend the lived experiences of ten nurses working in a hospital's palliative care department in Spain. Hermeneutic analysis was employed to extract patterns and insights from their experiences. The COREQ checklist was used to report this study. FINDINGS: Palliative care nurses perceived insufficient preparation in emotional management, grappling with complex family interactions and unique work dynamics. They highlighted the significance of self-protection strategies, experience, clinical sessions, and external resources. Limited training in emotional resilience and challenges posed by the COVID-19 pandemic emerged as organisational barriers. Nurses expressed a desire for enhanced training and resources. CONCLUSION: The study uncovered a deficiency in the emotional preparedness of palliative care nurses, impacting their professional and personal lives. Despite positive aspects, the emotional toll necessitates attention and intervention. IMPLICATIONS FOR NURSING POLICY: Comprehensive emotional training for palliative care nurses, addressing barriers, providing resources, and acknowledging emotional labour is necessary. Reinstating paused training sessions and considering specific challenges like those posed by the pandemic are vital. Supporting nurses in their professional and private lives is crucial for sustaining quality care in palliative care departments.

The overlooked functions of trichomes: Water absorption and metal detoxication.

Trichomes are epidermal outgrowths on plant shoots. Their roles in protecting plants against herbivores and in the biosynthesis of specialized metabolites have long been recognized. Recently, studies are increasingly showing that trichomes also play important roles in water absorption and metal detoxication, with these roles having important implications for ecology, the environment, and agriculture. However, these two functions of trichomes have been largely overlooked and much remains unknown. In this review, we show that the trichomes of 37 plant species belonging to 14 plant families are involved in water absorption, while the trichomes of 33 species from 13 families are capable of sequestering metals within their trichomes. The ability of trichomes to absorb water results from their decreased hydrophobicity compared to the remainder of the leaf surface as well as the presence of special structures for collecting and absorbing water. In contrast, the metal detoxication function of trichomes results not only from the good connection of their basal cells to the underlying vascular tissues, but also from the presence of metal-chelating ligands and transporters within the trichomes themselves. Knowledge gaps and critical future research questions regarding these two trichome functions are highlighted. This review improves our understanding on trichomes.

Leaf surface features of maize cultivars and response to foliar phosphorus application: effect of leaf stage and plant phosphorus status.

Soil phosphorus (P) application is the most common fertilisation technique but may involve constraints due to chemical fixation and microbial immobilisation. Furthermore, excessive P fertilisation leads to P runoff into water bodies, threatening ecosystems, so targeted foliar P fertilisation is an interesting alternative. This study aimed to determine the importance of leaf surface characteristics for foliar P uptake in P-deficient maize (Zea mays L.). The leaf surface of four maize cultivars was characterised by electron microscopy, Fourier transform infrared spectroscopy and contact angle measurements. Uptake of foliar-applied P by maize cultivars was estimated, measuring also leaf photosynthetic rates after foliar P spraying. Plants of cultivar P7948 were found to be wettable from the 4th leaf in acropetal direction, whereas other cultivars were unwettable until the 6th leaf had developed. Minor variations in stomatal number and cuticle composition were recorded, but no differences in foliar P absorption were observed between cultivars. Nevertheless, cultivars showed variation in the improvement of photosynthetic capacity following foliar P application. Phosphorus deficiency resulted in ultrastructural disorganisation of mesophyll cells and chloroplasts, which impaired photosynthetic performance, yet there was no effect on stomatal frequency and leaf wettability. This study provides new insights into the influence of P deficiency and cultivar on leaf surface characteristics, foliar P uptake and its effect on physiological processes. Understanding the relationships between leaf characteristics and P uptake allows a more targeted evaluation of foliar P fertilisation as an application technique and contributes to the understanding of foliar uptake mechanisms.

Effect of Rim-Off Deep Lateral Orbital Decompression on Interpalpebral Fissure Shape.

PURPOSE: The purpose of this study is to compare the palpebral fissure shape after rim-off deep lateral decompression with and without restoration of the lateral orbital rim. METHODS: Retrospective cross-sectional quantitative analysis of the palpebral fissure images of 17 patients (25 eyes) who underwent rim-off deep lateral orbital decompression without repositioning of the rim (G1) and of 20 patients (34 eyes) operated with rim restoration. Quantification of palpebral fissure images included MRD 1 and MRD 2 , two lateral mid-pupil lid margin (MPD) distances, the width of the palpebral fissure, and the height and shape of the lateral canthus. RESULTS: Proptosis reduction did not differ significantly between G1 and G2. In both groups, decompression reduced the mean values of the MRD 1 and MRD 2 , the lateral height of the upper eyelid, and the height and angle of the lateral canthus. The palpebral fissure width and lateral height of the lateral lower eyelid were not affected. There was no significant difference between the mean changes of G1 and G2. Multivariate analysis showed that the lateral canthus decrease was correlated with changes in MRD 1 and MRD 2 . CONCLUSIONS: Small changes in palpebral fissure shape after deep lateral decompression are not dependent on the presence or absence of the lateral rim.

The Early-Onset Alzheimer's Disease Whole-Genome Sequencing Project: Study design and methodology.

INTRODUCTION: Sequencing efforts to identify genetic variants and pathways underlying Alzheimer's disease (AD) have largely focused on late-onset AD although early-onset AD (EOAD), accounting for ∼10% of cases, is largely unexplained by known mutations, resulting in a lack of understanding of its molecular etiology. METHODS: Whole-genome sequencing and harmonization of clinical, neuropathological, and biomarker data of over 5000 EOAD cases of diverse ancestries. RESULTS: A publicly available genomics resource for EOAD with extensive harmonized phenotypes. Primary analysis will (1) identify novel EOAD risk loci and druggable targets; (2) assess local-ancestry effects; (3) create EOAD prediction models; and (4) assess genetic overlap with cardiovascular and other traits. DISCUSSION: This novel resource complements over 50,000 control and late-onset AD samples generated through the Alzheimer's Disease Sequencing Project (ADSP). The harmonized EOAD/ADSP joint call will be available through upcoming ADSP data releases and will allow for additional analyses across the full onset range. HIGHLIGHTS: Sequencing efforts to identify genetic variants and pathways underlying Alzheimer's disease (AD) have largely focused on late-onset AD although early-onset AD (EOAD), accounting for ∼10% of cases, is largely unexplained by known mutations. This results in a significant lack of understanding of the molecular etiology of this devastating form of the disease. The Early-Onset Alzheimer's Disease Whole-genome Sequencing Project is a collaborative initiative to generate a large-scale genomics resource for early-onset Alzheimer's disease with extensive harmonized phenotype data. Primary analyses are designed to (1) identify novel EOAD risk and protective loci and druggable targets; (2) assess local-ancestry effects; (3) create EOAD prediction models; and (4) assess genetic overlap with cardiovascular and other traits. The harmonized genomic and phenotypic data from this initiative will be available through NIAGADS.

Alterations in p53, Microsatellite Stability and Lack of MUC5AC Expression as Molecular Features of Colorectal Carcinoma Associated with Inflammatory Bowel Disease.

Colitis-associated colorectal carcinoma (CAC) occurs in inflammatory bowel disease (IBD) because of the "chronic inflammation-dysplasia-cancer" carcinogenesis pathway characterized by p53 alterations in the early stages. Recently, gastric metaplasia (GM) has been described as the initial event of the serrated colorectal cancer (CRC) process, resulting from chronic stress on the colon mucosa. The aim of the study is to characterize CAC analyzing p53 alterations and microsatellite instability (MSI) to explore their relationship with GM using a series of CRC and the adjacent intestinal mucosa. Immunohistochemistry was performed to assess p53 alterations, MSI and MUC5AC expression as a surrogate for GM. The p53 mut-pattern was found in more than half of the CAC, most frequently stable (MSS) and MUC5AC negative. Only six tumors were unstable (MSI-H), being with p53 wt-pattern (p = 0.010) and MUC5AC positive (p = 0.005). MUC5AC staining was more frequently observed in intestinal mucosa, inflamed or with chronic changes, than in CAC, especially in those with p53 wt-pattern and MSS. Based on our results, we conclude that, as in the serrated pathway of CRC, in IBD GM occurs in inflamed mucosa, persists in those with chronic changes and disappears with the acquisition of p53 mutations.

Foliar water and solute absorption: an update.

The absorption of water and solutes by plant leaves has been recognised since more than two centuries. Given the polar nature of water and solutes, the mechanisms of foliar uptake have been proposed to be similar for water and electrolytes, including nutrient solutions. Research efforts since the 19th century focussed on characterising the properties of cuticles and applying foliar sprays to crop plants as a tool for improving crop nutrition. This was accompanied by the development of hundreds of studies aimed at characterising the chemical and structural nature of plant cuticles from different species and the mechanisms of cuticular and, to a lower extent, stomatal penetration of water and solutes. The processes involved are complex and will be affected by multiple environmental, physico-chemical and physiological factors which are only partially clear to date. During the last decades, the body of evidence that water transport across leaf surfaces of native species may contribute to water balances (absorption and loss) at an ecosystem level has grown. Given the potential importance of foliar water absorption for many plant species and ecosystems as shown in recent studies, the aim of this review is to first integrate current knowledge on plant surface composition, structure, wettability and physico-chemical interactions with surface-deposited matter. The different mechanisms of foliar absorption of water and electrolytes and experimental procedures for tracing the uptake process are discussed before posing several outstanding questions which should be tackled in future studies.

Upper Eyelid Contour Changes After Orbital Decompression in Graves Orbitopathy.

PURPOSE: To evaluate the effect of orbital decompression on the upper eyelid contour. METHODS: A paired cross-sectional analysis of the upper eyelid contour was performed for 103 eyes of 66 patients who underwent orbital decompression. A control group of 26 normal subjects was also included. The eyelid contour of all participants were measured with Bézier lines adjusted to the eyelid contour and 9 midpupil eyelid margin (MPD) distances from a horizontal line bisecting the pupil. One central, corresponding to the margin reflex distance (MRD 1), and 8 equally distributed medially and laterally at 20% of the interval between the lines. Patients were classified as with flare if the height of the most lateral MPD relative to the MRD 1 was above the upper limit of the controls. RESULTS: Preoperatively 63 of the 103 contours were classified as flare + (F+). After decompression MRD1 showed a mean decrease of 0.4 mm and the location of the contour shifted 0.8 mm medially. These changes were not correlated with proptosis reduction. Orbital decompression decreased the lateral curvature of the contours especially for the F+ lids. In 40% of the F+ eyelids the flare sign disappeared after decompression. CONCLUSIONS: Orbital decompression affects the lateral eyelid contour and diminishes the amount of lateral eyelid retraction surgery necessary to correct the flare sign. In 40% of the patients, the eyelid contour is normalized with proptosis reduction only.

Objective assessment of eyelid position and tear meniscus in facial nerve palsy.

PURPOSE: To evaluate lower lid position and tear meniscus in peripheral idiopathic facial nerve palsy (FNP). METHODS: A prospective study enrolled patients with peripheral idiopathic FNP and epiphora. Data were collected on patient demographics, House-Brackmann (HB) scale, digital photographs of the face, and tear meniscus at the 1st, 30, and 90 day after onset of FNP. Marginal reflex distance to the upper (MRD1) and lower eyelid (MRD2) were evaluated using ImageJ software. Anterior segment optical coherence tomography (OCT) was performed to measure the tear menis- cus. P< .05 was considered statistically significant. RESULTS: Sixteen patients were evaluated. The HB scale at presentation was grade III in six patients (37.5%). At 90 day, nine patients (56.25%) were grade I-normal. Three (18.7%) had upper lid retraction, three (18.7%) upper eyelid asymmetry and 7 (43.75%), lower eyelid retraction. The difference between MRD2-FNP with MRD2-healthy side was 0.51 ± 1.9 mm at the 1st visit, decreasing to 0.09 ± 1.47 mm at 90 days (P= .877). Tear meniscus measurements were significantly higher in FNP at the 1st visit (P= .001). The decrease in MRD2 was statistically correlated with the reduction of the tear meniscus area (TMA) (r = 0.67; P= .007) at 90 days. No correlation was found between HB and TMA. There is a difference in TMA between age groups at the 1st day(p= .009). Eldest group had higher HB scales. CONCLUSION: Quantitative evaluation of eyelid position and tear meniscus are effective to document the evolution of FNP and can serve as a clue of orbicularis recovery.

Non-glandular trichomes of sunflower are important in the absorption and translocation of foliar-applied Zn.

Trichomes are potentially important for absorption of foliar fertilizers. A study has shown that the non-glandular trichromes (NGTs) of sunflower (Helianthus annuus) accumulated high concentrations of foliar-applied zinc (Zn); however, the mechanisms of Zn accumulation in the NGTs and the fate of this Zn are unclear. Here we investigated how foliar-applied Zn accumulates in the NGTs and the subsequent translocation of this Zn. Time-resolved synchrotron-based X-ray fluorescence microscopy and transcriptional analyses were used to probe the movement of Zn in the NGTs, with the cuticle composition of the NGTs examined using confocal Raman microscopy. The accumulation of Zn in the NGTs is both an initial preferential absorption process and a subsequent translocation process. This preferred absorption is likely because the NGT base has a higher hydrophilicity, whilst the subsequent translocation is due to the presence of plasmodesmata, Zn-chelating ligands, and Zn transporters in the NGTs. Furthermore, the Zn sequestered in the NGTs was eventually translocated out of the trichome once the leaf Zn concentration had decreased, suggesting that the NGTs are also important in maintaining leaf Zn homeostasis. This study demonstrates for the first time that trichomes have a key structural and functional role in the absorption and translocation of foliar-applied Zn.

One Triangle-Blepharoplasty Flap for Anterior Lamellae Pretarsal Defects on the Upper Eyelid.

PURPOSE: The aim of this study is to present the outcomes of one triangle blepharoplasty flap upper eyelid (UE) reconstruction. It is a hardly recognized technique used to repair anterior lamella pretarsal defects resulting from the removal of lesions on the UE. METHODS: Retrospective review of three excised lesions reconstructed with one triangle-blepharoplasty flap technique between 2017 and 2020 at Río Hortega University Hospital in Valladolid, Spain. It is a technique to reconstruct wide-based anterior lamella UE lesions, 25% to 50% UE length. Demographic characteristics, histology results and complications are presented. RESULTS: Medical records of three patients have been reviewed with a minimum follow-up of 6 months (mean follow up of 16 months). The patient's average age was 67 years. Histology results were three seborrheic keratosis. There were no intra or post-surgical complications and all had good functional and aesthetic upper lid results. CONCLUSIONS: The reconstruction of pretarsal lesions limited to the anterior lamella of the UE using one triangle-blepharoplasty flap is a technique with good functional and aesthetic results.

Microbial processing of plant remains is co-limited by multiple nutrients in global grasslands.

Microbial processing of aggregate-unprotected organic matter inputs is key for soil fertility, long-term ecosystem carbon and nutrient sequestration and sustainable agriculture. We investigated the effects of adding multiple nutrients (nitrogen, phosphorus and potassium plus nine essential macro- and micro-nutrients) on decomposition and biochemical transformation of standard plant materials buried in 21 grasslands from four continents. Addition of multiple nutrients weakly but consistently increased decomposition and biochemical transformation of plant remains during the peak-season, concurrent with changes in microbial exoenzymatic activity. Higher mean annual precipitation and lower mean annual temperature were the main climatic drivers of higher decomposition rates, while biochemical transformation of plant remains was negatively related to temperature of the wettest quarter. Nutrients enhanced decomposition most at cool, high rainfall sites, indicating that in a warmer and drier future fertilized grassland soils will have an even more limited potential for microbial processing of plant remains.

Prevalence of obesity and diabetes in the socioeconomic transition of rural Mayas of Yucatan from 1962 to 2000.

Background: The Mayas of the State of Yucatan in Mexico are the only aboriginal group with obesity and diabetes data before 1997. Objective: To analyze socioeconomic trends associated with the increase in obesity and diabetes seen in rural Yucatan from 1962 to 2000. Methods: Body weight, height and venous Fasting Blood Glucose (FBG) were measured in 263 rural Maya adults participating in a 2000 nutrition survey. Results: Diabetes (FBG > 125 mg/dL) and obesity (BMI ≥ 30 kg/m2) were 10.6% and 35.7%, respectively. These results contrast with those of a 1962 survey where diabetic prevalence was 2.3% and 0% in women and men respectively, with widespread adult pellagra and malnutrition. An important socioeconomic transition that took place in Yucatan during this lapse appeared to be associated to the obesity and diabetes increase. Conclusions: Rural Yucatan evolved from malnutrition conditions to high prevalence of obesity and diabetes in less than 40 years. This change was associated with the transition from an agroindustry-based economy, characterized by high-energy expenditure and low protein intake, to lower energy requirements of a Government-subsidized economy with larger food supply.

Absorption and distribution of root, fruit, and foliar-applied 45 Ca in 'Clemenules' mandarin trees.

BACKGROUND: The mechanisms of calcium (Ca) absorption and transport in plants are still poorly understood. This study focused on assessing the absorption and distribution of Ca in different plant organs after root (soil), foliar, or fruit application to 6-year-old 'Clemenules' mandarin trees, grown in pots, using 45 Ca as a tracer. RESULTS: The rate of 45 Ca absorption and transportation in plant tissues varied according to the treatment method. The fruit and shoot Ca supply led to a rate of 97% to 98% 45 Ca retention in such organs. In Ca-treated fruits, 22% of the applied 45 Ca moved to the pulp and 78% remained in the flavedo and albedo. The fruit peel was examined by scanning electron microscopy and transmission electron microscopy (SEM and TEM) and variations were observed during fruit development. Following 45 Ca soil treatment, approximately 56% of 45 Ca activity was measured in the soil, with 19.5% determined in the roots, 14.6% in the trunks (90% in bark and sapwood and only 10% in heartwood), 9.6% in shoots, and 0.3% in fruits. CONCLUSION: Calcium mobility in 'Clemenules' mandarin trees is limited and depends on the mode of Ca fertilizer application. The distribution of Ca to and within the fruits may be limited during development because of structural and functional constraints. © 2020 Society of Chemical Industry.

[Early Clinical Diagnosis of Anti-NMDA Receptor Encephalitis: Case Series and Literature Review]. / Diagnóstico clínico temprano de la Encefalitis Anti-Receptor NMDA: Serie de casos y revisión bibliográfica.

Autoimmune encephalitis refers to a group of pathologies described in the last two decades, characterized by neuropsychiatric symptoms of subacute presentation, mediated by antibodies directed against neuronal membrane proteins. Within this group, encephalitis mediated by antibodies against the NMDA receptor of glutamate is a particular clinical entity, given that its expression is dominated by psychiatric symptoms that usually occur at the onset of the disease. In this paper we describe five cases of NMDA encephalitis in adult patients followed up in the last four years in a public hospital in the City of Buenos Aires, Argentina. We also include a review of the current literature. We emphasize the clinical description of the psychiatric symptoms of presentation, since these lead to the patient's first contact with the health system. Given the difficulty in our environment to implement the determination of autoantibodies, the ability to clinically recognize this pathology becomes paramount to establish an early preliminary diagnosis and not to delay immunosuppressive therapy, thus allowing for a better prognosis.

RECQL5: Another DNA helicase potentially involved in hereditary breast cancer susceptibility.

There is still around 50% of the familial breast cancer (BC) cases with an undefined genetic cause, here we have used next-generation sequencing (NGS) technology to identify new BC susceptibility genes. This approach has led to the identification of RECQL5, a member of RECQL-helicases family, as a new BC susceptibility candidate, which deserves further study. We have used a combination of whole exome sequencing in a family negative for mutations in BRCA1/2 throughout (BRCAX), in which we found a probably deleterious variant in RECQL5, and targeted NGS of the complete coding regions and exon-intron boundaries of the candidate gene in 699 BC Spanish BRCAX families and 665 controls. Functional characterization and in silico inference of pathogenicity were performed to evaluate the deleterious effect of detected variants. We found at least seven deleterious or likely deleterious variants among the cases and only one in controls. These results prompt us to propose RECQL5 as a gene that would be worth to analyze in larger studies to explore its possible implication in BC susceptibility.

Exome sequencing identifies ATP4A gene as responsible of an atypical familial type I gastric neuroendocrine tumour.

Gastric neuroendocrine tumours (NETs) arise from enterochromaffin-like cells, which are located in oxyntic glands within the stomach. Type I tumours represent 70-80% of gastric NETs and are associated with hypergastrinaemia, chronic atrophic gastritis and achlorhydria. Gastrin is involved in the endocrine regulation of gastric acid production. Most type I gastric NETs are sporadic, have a good prognosis and their genetic basis are unknown. We performed an exome sequencing study in a family with consanguineous parents and 10 children, five of whom were affected by type I gastric NET. Atypical clinical traits included an earlier age of onset (around 30 years), aggressiveness (three had nodal infiltration requiring total gastrectomy and one an adenocarcinoma) and iron-deficiency rather than megaloblastic anaemia. We identified a homozygous missense mutation in the 14th exon of the ATP4A gene (c.2107C>T), which encodes the proton pump responsible for acid secretion by gastric parietal cells. The amino acid p.Arg703Cys is highly conserved across species and originates a change of one of the transmembrane domains that avoids the liberation of protons from cells to stomach. This is consistent with the achlorhydria that was observed in the affected individuals. No germline or somatic mutations in the ATP4A gene were found in sporadic gastric NET patients. Based on the results of this large family, it seems that this atypical form of gastric NET has an earlier age of onset, behaves more aggressively and has atypical clinical traits that differentiated from other studied cases.

Characterisation of the novel deleterious RAD51C p.Arg312Trp variant and prioritisation criteria for functional analysis of RAD51C missense changes.

BACKGROUND: Despite a high prevalence of deleterious missense variants, most studies of RAD51C ovarian cancer susceptibility gene only provide in silico pathogenicity predictions of missense changes. We identified a novel deleterious RAD51C missense variant (p.Arg312Trp) in a high-risk family, and propose a criteria to prioritise RAD51C missense changes qualifying for functional analysis. METHODS: To evaluate pathogenicity of p.Arg312Trp variant we used sequence homology, loss of heterozygosity (LOH) and segregation analysis, and a comprehensive functional characterisation. To define a functional-analysis prioritisation criteria, we used outputs for the known functionally confirmed deleterious and benign RAD51C missense changes from nine pathogenicity prediction algorithms. RESULTS: The p.Arg312Trp variant failed to correct mitomycin and olaparib hypersensitivity and to complement abnormal RAD51C foci formation according to functional assays, which altogether with LOH and segregation data demonstrated deleteriousness. Prioritisation criteria were based on the number of predictors providing a deleterious output, with a minimum of 5 to qualify for testing and a PredictProtein score greater than 33 to assign high-priority indication. CONCLUSIONS: Our study points to a non-negligible number of RAD51C missense variants likely to impair protein function, provides a guideline to prioritise and encourage their selection for functional analysis and anticipates that reference laboratories should have available resources to conduct such assays.