Classification of PTEN germline non-truncating variants: a new approach to interpretation.

BACKGROUND: PTEN hamartoma tumour syndrome (PHTS) encompasses distinct syndromes, including Cowden syndrome resulting from PTEN pathogenic variants. Missense variants account for 30% of PHTS cases, but their classification remains challenging. To address these difficulties, guidelines were published by the Clinical Genome Resource PTEN Variant Curation Expert Panel. METHODS: Between 2010 and 2020, the Bergonie Institute reference laboratory identified 76 different non-truncating PTEN variants in 166 patients, 17 of which have not previously been reported. Variants were initially classified following the current guidelines. Subsequently, a new classification method was developed based on four main criteria: functional exploration, phenotypic features and familial segregation, in silico modelling, and allelic frequency. RESULTS: This new method of classification is more discriminative and reclassifies 25 variants, including 8 variants of unknown significance. CONCLUSION: This report proposes a revision of the current PTEN variant classification criteria which at present rely on functional tests evaluating only the phosphatase activity of PTEN and apply a particularly stringent clinical PHTS score.The classification of non-truncating variants of PTEN is facilitated by taking into consideration protein stability for variants with intact phosphatase activity, clinical and segregation criteria adapted to the phenotypic variability of PHTS and by specifying the allelic frequency of variants in the general population. This novel method of classification remains to be validated in a prospective cohort.

Association of CACNA1C polymorphisms (rs1006737, rs4765905, rs2007044) with schizophrenia: A meta-analysis and trial sequential analysis.

Schizophrenia is a complex neurological disorder characterized by significant impairment in the perception of reality and changes in behavior. Genetic and environmental factors influence the development of schizophrenia. CACNA1C, which encodes a subunit of a voltage-dependent calcium channel, has been associated with various neurological disorders, including schizophrenia. Several studies have been performed in different populations to explore the association of common genetic variants in the CACNA1C gene with susceptibility to the development of schizophrenia, but results remain contradictory. To draw a definitive conclusion on the association between CACNA1C polymorphisms and schizophrenia, we conducted a meta-analysis focusing on three commonly studied polymorphisms: rs1006737, rs4765905, and rs2007044. For the meta-analysis, a comprehensive literature search was performed using PubMed, Scopus, Science Direct and Google Scholar databases. Data was retrieved, and the meta-analysis was performed using CMA v4 software. The meta-analysis revealed a significant association between rs1006737 and rs2007044 and schizophrenia in the overall population, while no such association was found for rs4765905. Population-wise analysis suggested that all three polymorphisms were significantly associated with schizophrenia in the Asian population and that rs1006737 was significantly associated with schizophrenia in Europeans. We also performed a Trial Sequential Analysis (TSA), which supported our findings. Some report-based assay studies have suggested a role for these polymorphisms in schizophrenia, but further case-control studies are needed to confirm the association of rs4765905 and rs2007044 with the disorder.

Ulcerative colitis: molecular insights and intervention therapy.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by abdominal pain, diarrhea, rectal bleeding, and weight loss. The pathogenesis and treatment of UC remain key areas of research interest. Various factors, including genetic predisposition, immune dysregulation, and alterations in the gut microbiota, are believed to contribute to the pathogenesis of UC. Current treatments for UC include 5-aminosalicylic acids, corticosteroids, immunosuppressants, and biologics. However, study reported that the one-year clinical remission rate is only around 40%. It is necessary to prompt the exploration of new treatment modalities. Biologic therapies, such as anti-TNF-α monoclonal antibody and JAK inhibitor, primarily consist of small molecules targeting specific pathways, effectively inducing and maintaining remission. Given the significant role of the gut microbiota, research into intestinal microecologics, such as probiotics and prebiotics, and fecal microbiota transplantation (FMT) shows promising potential in UC treatment. Additionally, medicinal herbs, such as chili pepper and turmeric, used in complementary therapy have shown promising results in UC management. This article reviews recent findings on the mechanisms of UC, including genetic susceptibility, immune cell dynamics and cytokine regulation, and gut microbiota alterations. It also discusses current applications of biologic therapy, herbal therapy, microecologics, and FMT, along with their prospects and challenges.

Lynch syndrome diagnostic testing pathways in endometrial cancers: a nationwide English registry-based study.

BACKGROUND: For female patients with Lynch syndrome (LS), endometrial cancer (EC) is often their first cancer diagnosis. A testing pathway of somatic tumour testing triage followed by germline mismatch repair (MMR) gene testing is an effective way of identifying the estimated 3% of EC caused by LS. METHODS: A retrospective national population-based observational study was conducted using comprehensive national data collections of functional, somatic and germline MMR tests available via the English National Cancer Registration Dataset. For all EC diagnosed in 2019, the proportion tested, median time to test, yield of abnormal results and factors influencing testing pathway initiation were examined. RESULTS: There was an immunohistochemistry (IHC) or microsatellite instability (MSI) test recorded for 17.8% (1408/7928) of patients diagnosed with EC in 2019. Proportions tested varied by Cancer Alliance and age. There was an MLH1 promoter hypermethylation test recorded for 43.1% (149/346) of patients with MLH1 protein IHC loss or MSI. Of patients with EC eligible from tumour-testing, 25% (26/104) had a germline MMR test recorded. Median time from cancer diagnosis to germline MMR test was 315 days (IQR 222-486). CONCLUSION: This analysis highlights the regional variation in recorded testing, patient attrition, delays and missed opportunities to diagnose LS, providing an informative baseline for measuring the impact of the national guidance from the National Institute for Health and Care Excellence on universal reflex LS testing in EC, implemented in 2020.

Gene-diet interactions in carbonated sugar-sweetened beverage consumption and metabolic syndrome risk: A machine learning analysis in a large hospital-based cohort.

BACKGROUND AND AIM: Carbonated sugar-sweetened beverages (CSSB) intake has been increasingly linked to metabolic diseases. To investigate the association between CSSB intake and metabolic syndrome (MetS) risk, and the interaction between genetic predisposition to CSSB intake and dietary patterns. METHODS: We examined a hospital-based cohort of 57,940 participants, categorized into low-CSSB (n=52,848) and high-CSSB (n=5,092) groups based on a 50 ml daily consumption cutoff. A genome-wide association study (GWAS) identified single-nucleotide polymorphisms (SNPs) associated with CSSB intake, and SNP-SNP/SNP-environment interactions were explored. Using XGBoost and deep neural network (DNN) approaches, we developed prediction models for CSSB intake. RESULTS: The low- and high-CSSB groups daily consumed an average of 0.56 and 8.91 g sugar from the soda, respectively. The high-CSSB group had unhealthy dietary habits and a lower intake of carotenoids, folate, vitamins C and D, calcium, flavonoids, and phenols than the low-CSSB group, consistent with the results of the prediction models. A polygenic risk score (PRS) based on 6 selected SNPs, linked to genes involved in obesity, diabetes, and nervous system disorders, showed the strongest association with CSSB intake and insulin resistance. Notably, carbohydrate, fat, and Western-style diet (WSD) intake interacted with the PRS, with lower carbohydrate and higher fat and WSD intakes associated with a stronger PRS-sugar intake relationship. The prediction models by XGboost and DNN mainly included dietary factors to explain CSSB intake. CONCLUSIONS: A significant interplay between genetic predisposition and poor dietary habits, particularly increased CSSB intake associated with WSD, contributed to MetS risk. It suggested that personalized dietary interventions based on genetic profiles could mitigate MetS risk, especially in populations transitioning to Westernized diets.

Stair climbing and risk of incident atrial fibrillation: Effect modulated by sex, genetic predisposition, and cardiorespiratory fitness.

BACKGROUND AND AIMS: Stair climbing, a straightforward and impactful form of physical activity, has shown potential in reducing risks of cardiovascular disease and mortality. However, its association with the development of atrial fibrillation (AF) remains largely unexplored. METHODS AND RESULTS: 451,089 participants (mean age 56.5 years) without cardiovascular disease (year 2006-2010) were included from the UK Biobank study. Stair climbing data was collected through touchscreen questionnaire. AF cases were identified using ICD-10 code: I48 and were followed until February 1, 2022. Models adjusted for traditional cardiovascular risk factors. Over a median follow-up of 12.6 years, 23,660 (5.2 %) participants experienced new-onset AF. In multivariable-adjusted models, climbing 10-50, 60-100, 110-150, and ≥160 steps of stairs per day were associated with significant reductions in the risk of AF, compared to not climbing any stairs. The risk reduction appeared more pronounced in women than in men (P for interaction = 0.09). When compared to participants who climbed no stairs, the HRs for those who climbed 110-150 steps of stairs per day were 0.69 (95 % CI: 0.58-0.82) among those with low cardiorespiratory fitness, 0.71 (95 % CI: 0.57-0.88) among those with intermediate cardiorespiratory fitness, and 0.83 (95 % CI: 0.64-1.07) among those with high cardiorespiratory fitness. CONCLUSIONS: Climbing stairs was associated with a reduction in AF risks. Significant interaction between cardiorespiratory fitness and stair climbing associated with incident AF was observed. Findings suggest that promoting regular stair climbing could be a potential target for preventing AF onset.

Investigation of the association of the MLPH gene with seasonal canine flank alopecia in Rhodesian Ridgeback dogs.

BACKGROUND: Canine flank alopecia (CFA) is a skin condition in dogs characterized by non-inflammatory, seasonally recurring episodes of localized hair loss and often hyperpigmentation of the affected skin. A genetic basis is suspected because of the predisposition in certain breeds, such as the Rhodesian Ridgeback (RR). This study investigated the possible role of the canine melanophylin (MLPH) gene in CFA among RRs through pedigree analysis and MLPH genotyping. RESULTS: We included 24 CFA-affected and 12 non-CFA-affected control RRs. Pedigree analysis revealed inbreeding loops and close family relationships among the CFA-affected dogs, indicating the potential heritability of CFA. MLPH genotyping revealed 3/24 (12.5%) affected dogs and 1/12 (8.3%) control dogs to be heterozygous (Dd) for the dilute (d) allele, indicating no difference between these groups. None of the dogs were found to be homozygous (dd). Statistical analysis did not reveal an association between the MLPH-d allele and CFA. CONCLUSIONS: The familial patterns among affected RRs observed through pedigree analysis suggest a potential genetic component in CFA. However, our findings from the MLPH genotyping did not reveal that the MLPH gene is involved in this skin condition in RRs. However, further genetic studies are needed to clarify the etiology of CFA in RR dogs.

Canine Flank Alopecia is an undesired skin condition in dogs. Affected dogs lose hair, typically on one or both sides of the body, without signs of any other skin disease. The well-demarcated bald patches are often hyperpigmented and non-itchy. The surrounding hair and skin are normal. Hair will usually regrow within 3­8 months after the onset of hair loss, but bald patches will often recur every year. Because some breeds, such as the Rhodesian Ridgeback, are at risk of developing this trait, it is suspected that this condition may have a genetic basis.This study aimed to determine whether a specific gene (the canine Menalophylin gene) may play a role in canine flank alopecia among Rhodesian Ridgebacks. We used pedigree analysis to explore the relationships between family members and disease inheritance patterns within families. We used MLPH genotyping to examine differences in the occurrence of this gene between affected Rhodesian Ridgebacks and healthy ones. In this study, we included 24 affected and 12 healthy control Rhodesian Ridgebacks. The pedigree analysis of the affected dogs revealed close family ties and inbreeding loops. This finding points to a possible heritability of canine flank alopecia. This genetic study did not reveal that the MLPH gene is involved in this skin condition. The cause of CFA may be multifactorial, with both genetic and environmental factors playing a role.We recommend further investigation of the genetic and environmental basis of Canine Flank Alopecia in Rhodesian Ridgebacks. Deeper knowledge could help develop breeding strategies to minimize the frequency of this undesirable skin trait within the Rhodesian Ridgebacks population.

Zinc, copper, and selenium levels in vitiligo: a systematic review and meta-analysis.

Vitiligo is a dermatological disease characterized by loss of melanocytes, causing non-scaly white macules on the skin. Zinc, copper, and selenium are important micronutrients that play a role in the normal functioning of the body and have been found to potentially aid in vitiligo treatment, although the relationship between their serum levels and vitiligo is not yet fully understood. This is a systematic review aimed at assessing the levels of serum zinc, copper, and selenium and their association with vitiligo. This review was performed following the Preferred Reporting Items of the systematic Review and Meta-Analysis (PRISMA) checklist and Cochrane guidelines. A comprehensive literature search was conducted on PubMed, Google Scholar and 41 studies published between 1970 and 2022 including 3353 vitiligo cases and 10,638 controls were included in the meta-analysis conducted from August 2022 till September 2023. The quality of the studies was assessed using the National Heart Lung and Blood Institute Study Quality Assessment tool, and the risk of bias was represented using the RobVis tool. The statistical analysis was performed using Review Manager (RevMan) Version 5.4. This meta-analysis indicate a significant decline in serum zinc levels (Z = 4.97; P < 0.0001; SMD = - 0.86; 95% CI - 1.19 to - 0.52) in vitiligo group with high statistical heterogeneity (Tau2 = 0.74; Chi2 = 513.95, d.f. = 26 [P < 0.00001]; I2 = 95%). Similarly for serum copper levels there was decline (Z = 2.43; P < 0.0001; SMD = - 0.50; 95% confidence interval [CI] - 0.91 to - 0.10) in vitiligo group and high statistical heterogeneity (Tau2 = 0.92; Chi2 = 475.10, d.f. = 22 [P < 0.00001]; I2 = 95%). On the other hand, there was a increase of serum selenium levels in the vitiligo group (Z = 0.56; P < 0.0001; SMD = 0.23; 95% confidence interval [CI], 0.58 to 1.04) and the results reveals high statistical heterogeneity among studies (Tau2 = 1.93; Chi2 = 406.44, d.f. = 11 [P < 0.00001]; I2 = 97%) in vitiligo patients compared to healthy controls. Publication bias was not found for the studies analysed. This study analyses the association of serum micronutrient levels and vitiligo among patients and controls from published research along with sub-group analysis specific to Asian populations using a meta-analysis. Low serum levels of Zinc and copper and high selenium levels are associated with Vitiligo.

Genetic Predisposition of Different Social Status Indicators in Men and Women.

Although there is evidence that social status has a genetic basis, it is less known whether the genetic predisposition differs between men and women as well as among different status indicators and whether there are any intercorrelations among predispositions of status indicators. We therefore investigated the genetic predisposition for different indicators of social status separately for men and women, using polygenic scores obtained from the Wisconsin Longitudinal Study. We used multivariate polygenic regression of 7 different social status indicators on a total of 24 different polygenic scores. We find that in both men and women, wages and education show more associations with polygenic scores than the other status indicators. Also, the genetic predispositions for education and wages are correlated in both men and women, whereas in men more than in women, the genetic predispositions seem to cluster into wages and education on the one hand, and status indicators of position in the hierarchy, on the other hand, with being in a management position somewhere in between. These findings are consistent with an assumption of two different forms of selection pressure associated with either cognitive skill or dominance, which holds true particularly in men. We conclude that the genetic predisposition to higher social status may have changed even though the importance of the cultural trait of social status may have been very constant. Social status may thus be an example of a social trait of constant importance, but with a changing genetic predisposition.

Exome Sequencing of a Blastomycosis Case-Control Cohort From Manitoba and Northwestern Ontario, Canada.

BACKGROUND: Blastomycosis is a pulmonary disease caused by Blastomyces spp., a group of pathogenic dimorphic fungi endemic to a number of geographic regions, specifically Manitoba and northwestern Ontario, Canada. Immunosuppression is a major risk factor affecting disease susceptibility, yet host immunity is not well understood. Genetic immunodeficiencies can also influence disease, with variants in IL6, GATA2 and VDBP shown to influence susceptibility. Additional genetic factors in disease susceptibility and severity remain undetected. Our study seeks to identify potential genetic risk factors in a blastomycosis case-control cohort from Manitoba and northwestern Ontario, Canada. METHODS: Exomes from 18 blastomycosis cases and 9 controls were sequenced, variants were identified and filtered for accuracy and quality. We performed candidate gene prioritisation and variant aggregation to identify genetic associations and explored the full exome dataset. RESULTS: Ninety-nine genetic variants in 42 candidate genes were identified in the exome dataset. No variants associated with susceptibility were identified in a single-variant analysis although two non-synonymous variants in TYK2 were enriched among cases suggesting a possible role in susceptibility. Gene-based association analysis found variants in TLR1 enriched in controls (p = 0.024) suggesting a possible protective effect. Gene cluster analysis identified genetic variants in genes of chromatin remodelling, proteasome and intraflagellar transport significantly enriched in cases (false discovery rates < 14%). CONCLUSIONS: The findings in this study show novel associations with blastomycosis susceptibility. A better understanding of host immunity and genetic predisposition to Blastomyces infection can help to inform clinical practice for improved outcomes.

Anemia, blood cell indices, genetic correlations, and brain structures: A comprehensive analysis of roles in Parkinson's disease risk.

INTRODUCTION: Anemia may contribute significantly to the onset of Parkinson's disease (PD). Current research on the association between anemia and PD risk is inconclusive, and the relationships between anemia-related blood cell indices and PD incidence require further clarification. This study aims to investigate the relationships between anemia, blood cell indicators, and PD risk using a thorough prospective cohort study. METHODS: We used data from the UK Biobank, a prospective cohort study of 502,649 participants, and ultimately, 365,982 participants were included in the analysis. Cox proportional hazards models were utilized to adjust for confounding factors, aiming to thoroughly explore the associations between anemia and blood cell indices with the risk of incident PD. The interaction between anemia and Polygenic Risk Score (PRS) for PD was also examined. Linear regression and mediation analyses assessed potential mechanisms driven by brain structures, including grey matter volume. RESULTS: During a median follow-up of 14.24 years, 2513 participants were diagnosed with PD. Anemia considerably increased PD risk (hazard ratio [HR] 1.98, 95 % confidence interval [CI]: 1.81-2.18, P < 0.001) after adjustments. Those with high PRS for anemia had an 83 % higher PD incidence compared to low PRS participants. Sensitivity analyses confirmed result robustness. Linear regression showed that anemia correlated with grey matter volumes and most white matter tracts. Furthermore, mediation analyses identified that the volume of grey matter in Thalamus mediates the relationship between anemia and PD risk. CONCLUSION: In summary, we consider there to be a substantial correlation between anemia and increased PD risk.

Necrotizing Enterocolitis: A Current Understanding and Challenges for the Future.

This perspective reviews the definition and current understanding of necrotizing enterocolitis and evaluates a future prevention approach to this multifactorial disease. An overview of the prevention approach in general is presented, where key aspects and emerging criticisms are identified. In addition, key elements of early diagnosis and treatment are presented, together with some of their challenges and ambiguities. Moreover, it concludes with emerging questions from the global community to reach a consensus on the definition, diagnosis, and management of necrotizing enterocolitis disease.

The first reported familial case of statin-induced immune-mediated necrotizing myopathy associated with anti-hydroxy-3-methylglutaryl-CoA reductase autoantibodies and HLA DRB1*11:01.

Immune-mediated necrotizing myopathy (IMNM) is a rare type of auto-immune myositis, characterized by symmetric muscle pain, proximal weakness, elevated serum CK levels and pathologic findings of necrotized muscle fibers. IMNM may be seronegative, associated with anti-signal recognition particle (SRP) antibodies or anti-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) antibodies, the last widely related with statin use. This last entity affects only 2 to 3 of 100,000 patients under statins. Recently, patients carrying the class II human leukocyte antigen (HLA) DRB1*11:01 were identified to be more at risk to present IMNM with anti-HMGCR antibodies. We describe the case of a daughter and father diagnosed with HMGCR-IMNM and both carrying HLA DRB1*11:01. To our knowledge, it is the first familial case reported in the literature.

Synchronous Seminoma of Testis and Renal Cell Carcinoma: A Rare Case Report.

Background and Objectives: Seminoma is the most common solid malignant tumour in young men. Clear-cell kidney carcinoma is the most common malignancy of the genitourinary tract. However, the synchronous occurrence of both of these tumours is rare. Case presentation: We present the case of a 36-year-old patient who presented to a medical facility at the end of 2019 with an enlarged right testicle. A unilateral orchofuniculectomy was performed, and a mass measuring 30 cm was removed. During histological examination, testicular seminoma pT2, R0, was diagnosed. An abdominal computed tomography (CT) scan showed a 6.4 cm × 6.8 cm × 6.7 cm tumour in the right kidney and a metastatic-like lesion in the right adrenal gland. A right nephrectomy and an adrenalectomy and paraaortic and paracaval lymphadenectomies were performed. A histological evaluation confirmed the presence of clear-cell renal carcinoma pT2aR0 G2, adrenal hyperplasia, and seminoma metastases in the removed lymph node. Chemotherapy with a Bleomycin, Etoposide, and Cisplatin (BEP) regimen was carried out. Three years after the last cycle of chemotherapy, a follow-up CT scan showed metastases in the left kidney, the right ischium, and the right lung. A well-differentiated clear-cell carcinoma G1 of the left kidney and metastasis of clear-cell carcinoma G2 in the right ischium were confirmed after the biopsy, and no tumour lesions were found in the lung tissue specimen. Treatment with targeted therapy with Sunitinib was started because the risk was favourable according to the Heng criteria. Genetic testing was performed, and the following genes were analysed: VHL, BAP1, CHEK2, FH, MET, MUTYH, APC, and STK11. The testing did not reveal any pathogenic or potentially pathogenic mutations or sequence changes of unknown clinical significance in the genes analysed. Conclusions: According to the authors, the occurrence of synchronous primary tumours is linked to one's genetic predisposition. DNA sequencing of tumour tissue could provide more information on the corresponding aetiopathogenesis.

Association of Human Leukocyte Antigen Alleles with COVID-19 Severity and Mortality in a Spanish Population.

Background and Objectives: The aim of the following cross-sectional study is to determine the association between human leukocyte antigen (HLA) alleles and outcomes in patients presenting to the emergency department (ED) with SARS-CoV-2 infection. Methods and Materials: Genotyping was made using the Axiom Human Genotyping SARS-CoV-2 Research Array. Statistical analysis was made with Fisher's exact test and multivariable logistic regression, adjusted for sex, age and clinical variables. Results: Of 190 patients, 11.1% were discharged from the ED; 57.9% were admitted to the COVID-19 ward, without intensive care unit (ICU) admission; 15.3% survived an ICU admission; and 15.8% died. After multivariable analysis, two HLA alleles protected against hospital admission (HLA-C*05:01, adjusted odds ratio [aOR] 0.2, 95% confidence interval [CI] 0.055-0.731; and HLA-DQB1*02:02, aOR 0.046, CI 0.002-0.871) and one was associated with higher risk for ICU admission or death (HLA-DQA1*05:01, aOR 2.517, CI 1.086-5.833). Conclusions: In this population, HLA-C*05:01 and HLA-DQB1*02:02 are associated with a protective effect against hospital admission and HLA-DQA1*05:01 is associated with higher risk of ICU admission or death in the multivariable analysis. This may help stratify risk in COVID-19 patients.

Epidemiological and genetic aspects of pulmonary tuberculosis in Kazakhstan.

OBJECTIVE: Tuberculosis is a major health problem in many countries, including Kazakhstan. Host genetics can affect TB risk, and epidemiological and social factors may contribute to disease progression. Due to the high incidence of pulmonary tuberculosis in the country, our research aimed to study the epidemiological and genetic aspects of pulmonary tuberculosis in Kazakhstan. MATERIAL AND METHODS: 1026 participants of Central Asian origin were recruited in the study: 342 individuals diagnosed with active PTB, 342 household contacts, and 342 controls without a family history of TB. Genetic polymorphisms of selected genes were determined by real-time polymerase chain reaction. The association between the risk of pulmonary TB and polymorphisms was evaluated using logistic regression and assessed with the ORs and their corresponding 95 % CIs, and the significance level was determined as p < 0.05. RESULTS: Epidemiological data revealed that underweight BMI (χ² = 89.97, p < 0.001), employment (χ² = 39.28, p < 0.001), and diabetes (χ² = 12.38, p < 0.001) showed a significant association with PTB. A/T polymorphism of the IFG gene showed a lower risk, and A/A polymorphism showed an increased risk of susceptibility to TB. A/A polymorphism of the IFG gene was associated with an almost 3-fold increased risk of PTB, and A/T polymorphism of the IFG gene was associated with a decreased risk of PTB (OR = 0.67, 95 % CI = 0.49-0.92, p = 0.01). The analysis revealed a decreased risk of PTB for A/A polymorphism of the VDR ApaI (OR = 0.67, 95 % CI = 0.46-0.97, p < 0.05). A/A polymorphism of the TLR8 gene was associated with a 1.5-fold increased risk of PTB (OR = 1.53, 95 % CI = 1.00-2.33, p < 0.05). CONCLUSION: Results showed that gender, employment, underweight BMI and diabetes are associated with PTB incidence in our study cohort. The A/A genotype of the IFG (rs2430561) and an A/A genotype of the TLR8 (rs3764880) genes were associated with an increased risk of PTB. A/T polymorphism of the IFG (rs2430561) and A/A polymorphism of the VDR ApaI were associated with a decreased risk of PTB.

Cascade testing in mitochondrial diseases: a cross-sectional retrospective study.

BACKGROUND: Cascade testing can offer improved surveillance and timely introduction of clinical management for the at-risk biological relatives. Data on cascade testing and costs in mitochondrial diseases are lacking. To address this gap, we performed a cross-sectional retrospective study to provide a framework for cascade testing in mitochondrial diseases, to estimate the eligibility versus real-time uptake of cascade testing and to evaluate the cost of the genetic diagnosis of index cases and the cost of predictive cascade testing. METHODS: Data was collected through retrospective chart review. The variant inheritance pattern guided the identification of eligible first-degree relatives: (i) Males with mitochondrial DNA (mtDNA) single nucleotide variants (SNVs) - siblings and mothers. (ii) Females with mtDNA SNVs - siblings, mothers and offspring. (iii) Autosomal Dominant (AD) nuclear DNA (nDNA) variants - siblings, offspring and both parents. (iv) Autosomal Recessive (AR) nDNA variants - siblings. RESULTS: We recruited 99 participants from the Adult Mitochondrial Disease Clinic in Sydney. The uptake of cascade testing was 55.2% in the mtDNA group, 55.8% in the AD nDNA group and 0% in AR nDNA group. Of the relatives in mtDNA group who underwent cascade testing, 65.4% were symptomatic, 20.5% were oligosymptomatic and 14.1% were asymptomatic. The mean cost of cascade testing for eligible first-degree relatives (mtDNA group: $694.7; AD nDNA group: $899.1) was lower than the corresponding index case (mtDNA group: $4578.4; AD nDNA group: $5715.1) (p < 0.001). CONCLUSION: The demand for cascade testing in mitochondrial diseases varies according to the genotype and inheritance pattern. The real-time uptake of cascade testing can be influenced by multiple factors. Early diagnosis of at-risk biological relatives of index cases through cascade testing, confirms the diagnosis in those who are symptomatic and facilitates implementation of surveillance strategies and clinical care at an early stage of the disease.

Pathogenic Germline Variants in Uveal Melanoma Driver and BAP1-Associated Genes in Finnish Patients with Uveal Melanoma.

Uveal melanoma (UM) is a rare yet aggressive eye cancer causing over 50% mortality from metastasis. Familial UM, amounting to 1%-6% of patients in Finland and the United States, mostly lack identified genetic cause, while 8% show associations with other cancer syndromes. We searched novel genetic associations for predisposition to UM, additional to already studied BAP1 and MBD4, by using targeted amplicon sequencing of 19 genes associated with UM, BAP1, or renal cell carcinoma in 270 consecutively enrolled Finnish patients with UM. Key UM drivers GNAQ, GNA11, CYSLTR2, PLCB4, EIF1AX, and SF3B1 lacked pathogenic germline variants. One patient carried the pathogenic BRCA1 variant c.3626del p.(Leu1209*), and one harbored a novel truncating MET variant c.252C > G p.(Tyr84*), classified as likely pathogenic. FLCN and BRCA2, previously identified with pathogenic variants in patients with UM, did not have such variants in our cohort. Two patients were heterozygous for a pathogenic recessive BLM variant c.2824-2A > T. None of the carriers of identified variants had familial UM. We identified BRCA1 and MET as genes with pathogenic germline variants in Finnish UM patients, each with a frequency of 0.4% (95% confidence interval, 0-2).

Factors influencing prophylactic surgical intervention in women with genetic predisposition for breast cancer.

INTRODUCTION: In the United States, 5%-10% of breast cancer cases are due to genetic predisposition. Among this population, prophylactic mastectomy is viable risk-reducing option. OBJECTIVE: The objective of this study is to understand the timing to prophylactic mastectomy in patients with genetic predisposition to breast cancer and uncover factors influencing this decision. METHODS: This study is a retrospective review of patients diagnosed with genetic predisposition for breast cancer from 2010 to 2020. RESULTS: In a cohort of 506 patients with genetic predisposition for breast cancer, 154 (30.4%) underwent prophylactic mastectomy, the remainder opted for surveillance alone. The median time from diagnosis to mastectomy was 1.1 years (IQR, 0.5-3.1 years). During the surveillance period, 118 patients (33.5%) underwent breast biopsy. Of the patients with benign or atypical findings, 35 (36.8%) pursued prophylactic mastectomy, a median of 0.5 years (IQR, 0.2-1.6 years) after their gene diagnosis. The most common factor impacting the decision to undergo prophylactic mastectomy was having a family member with cancer (54.7%) followed by a personal diagnosis of other cancer(s) (27.5%). CONCLUSION: Understanding the factors influencing the decision to undergo prophylactic surgery will allow for more effective shared decision-making for primary care providers, breast surgeons, and reconstructive surgeons.