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AIMS: To evaluate insulin secretion and insulin resistance profiles in individuals with family history of prediabetes and type 2 diabetes. METHODS: This was a cross-sectional study to evaluate clinical and metabolic profiles between individuals with type 2 diabetes, prediabetes and their relatives. There were 911 subjects divided into five groups: (i) normoglycemic (NG), (ii) type 2 diabetes, (iii) prediabetes, (iv) first-degree relatives of patients with type 2 diabetes (famT2D), and (v) first-degree relatives of patients with prediabetes (famPD); anthropometrical, biochemical and nutritional evaluation, as well as insulin resistance and pancreatic beta cell function measurement was performed by oral glucose tolerance to compare between groups. RESULTS: The most prevalent type 2 diabetes risk factors were dyslipidemia (81%), family history of type 2 diabetes (76%), central obesity (73%), male sex (63%), and sedentary lifestyle (60%), and most of them were progressively associated to prediabetes and type 2 diabetes groups. Insulin sensitivity was lower in famT2D groups in comparison to NG group (p < 0.0001). FamPD and famT2D had a 10% lower pancreatic beta cell function (DI) than the NG group (NG group 2.78 ± 1.0, famPD 2.5 ± 0.85, famT2D 2.4 ± 0.75, p˂0.001). CONCLUSIONS: FamPD and famT2D patients had lower pancreatic beta cell function than NG patients, highlighting that defects in insulin secretion and insulin sensitivity appear long time before the development of hyperglycemia in patients genetically predisposed.

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INTRODUCTION: Hereditary angioedema (HAE) is a rare genetic disease characterized by submucosal and subcutaneous edema with high morbidity and possibility of mortality. This study presents the sociodemographic characteristics of a large Brazilian family with HAE. METHODS: Descriptive cross-sectional study with patients from two family branches coming from the same city and HAE diagnosis was carried out. Clinical, laboratory, and treatment data of patients have been collected. Genetic testing was performed on some individuals. Correlation tests and comparisons between variables were applied using IBM SPSS Statistics® 2.0 program. RESULTS: We provide a detailed characterization of two families affected by HAE due to C1-INH deficiency, residing in a small town in southern Brazil. These families harbor an identified mutation in the SERPING1 gene (c.1104del, p.Asp369ThrfsTer2). The mean age at HAE diagnosis was 16.7 (±14.0) years, with the mean onset of symptoms at 6.0 (±6.1) years of age. A correlation was observed between patients' current age and age at HAE diagnosis, with older patients being diagnosed later than younger individuals (p < 0.0001). On average, there were 16.8 emergency visits in the past year (±24.8), and 53.5% of patients reported at least one lifetime hospitalization. Notably, treatment modalities often diverged from consensus recommendations regarding optimal prophylaxis and management of HAE attacks. CONCLUSIONS: This study describes one of the largest known families with HAE in Brazil and highlights the significant impact of unfavorable social conditions on disease control.

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The greater muscle fiber cross-sectional area (CSA) is associated with greater skeletal muscle mass and strength, whereas muscle fiber atrophy is considered a major feature of sarcopenia. Muscle fiber size is a polygenic trait influenced by both environmental and genetic factors. However, the genetic variants underlying inter-individual differences in muscle fiber size remain largely unknown. The aim of our study was to determine whether 1535 genetic variants previously identified in a genome-wide association study of appendicular lean mass are associated with the CSA of fast-twitch muscle fibers (which better predict muscle strength) in the m. vastus lateralis of 148 physically active individuals (19 power-trained and 28 endurance-trained females, age 28.0 ± 1.1; 28 power-trained and 73 endurance-trained males, age 31.1 ± 0.8). Fifty-seven single-nucleotide polymorphisms (SNPs) were identified as having an association with muscle fiber size (p < 0.05). Of these 57 SNPs, 31 variants were also associated with handgrip strength in the UK Biobank cohort (n = 359,729). Furthermore, using East Asian and East European athletic (n = 731) and non-athletic (n = 515) cohorts, we identified 16 SNPs associated with athlete statuses (sprinter, wrestler, strength, and speed-strength athlete) and weightlifting performance. All SNPs had the same direction of association, i.e., the lean mass-increasing allele was positively associated with the CSA of muscle fibers, handgrip strength, weightlifting performance, and power athlete status. In conclusion, we identified 57 genetic variants associated with both appendicular lean mass and fast-twitch muscle fiber size of m. vastus lateralis that may, in part, contribute to a greater predisposition to power sports.

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This study aimed to investigate prognosis and survival differences in 82 breast cancer patients with germline pathogenic/likely pathogenic variants (PVs) treated and followed at the Breast Unit of the Instituto Nacional de Cancerología, Colombia (INC-C) between 2018 and 2021. Median age at diagnosis was 46 years, with 62.2% presenting locally advanced tumors, 47.6% histological grade 3, and 35.4% with triple-negative breast cancer (TNBC) subtype. Most carriers, 74.4% (61/82), had PVs in known breast cancer susceptibility genes (i.e., "associated gene carriers" group, considered inherited breast cancer cases): BRCA2 (30), BRCA1 (14), BARD1 (4), RAD51D (3), TP53 (2), PALB2 (2), ATM (2), CHEK2 (1), RAD51C (1), NF1 (1), and PTEN (1). BRCA1-2 represented 53.7%, and homologous recombination DNA damage repair (HR-DDR) genes associated with breast cancer risk accounted for 15.9%. Patients with PVs in non-breast-cancer risk genes were combined in a different category (21/82; 25.6%) (i.e., "non-associated gene carriers" group, considered other breast cancer cases). Median follow-up was 38.1 months, and 24% experienced recurrence, with 90% being distant. The 5-year Disease-Free Survival (DFS) for inherited breast cancer cases was 66.5%, and for other breast cancer cases it was 88.2%. In particular, for carriers of PVs in the BRCA2 gene, it was 37.6%. The 5-year Overall Survival (OS) rates ranged from 68.8% for those with PVs in BRCA2 to 100% for those with PVs in other HR-DDR genes. Further studies are crucial for understanding tumor behavior and therapy response differences among Colombian breast cancer patients with germline PVs.

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The aim of this study was to associate FGFR4 rs1966265 and rs351855 variants with colorectal cancer (CRC) in a Mexican population and to perform in silico analysis. Genomic DNA from 412 healthy individuals and 475 CRC patients was analyzed. In silico analysis was performed using the PolyPhen-V2, GEPIA, GTEx, and Cytoscape platforms. The GA genotype dominant model (GAAA) of rs1966265 and the AA genotype dominant and recessive models of rs351855 were identified as CRC risk factors (p < 0.05). CRC patients aged ≥ 50 years at diagnosis who consumed alcohol had a higher incidence of the rs351855 GA genotype than the control group (p < 0.05). Associations were observed between the rs1966265 GA genotype and patients with rectal cancer and stage III-IV disease. The rs351855 AA genotype was a risk factor for partial chemotherapy response, and the GA + AA genotype for age ≥ 50 years at diagnosis and rectal cancer was associated with a partial response to chemotherapy (p < 0.05). The AA haplotype was associated with increased susceptibility to CRC. In silico analysis indicated that the rs351855 variant is likely pathogenic (score = 0.998). Genotypic expression analysis in blood samples showed statistically significant differences (p < 0.05). EFNA4, SLC3A2, and HNF1A share signaling pathways with FGFR4. Therefore, rs1966265 and rs351855 may be potential CRC risk factors.

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OBJECTIVE: To determine a family aggregation pattern of Irritable Bowel Syndrome (IBS). DESIGN: it is a case-control study with a 1.2 ratio. SETTING: External consultation of a general family medicine practice. PARTICIPANTS: men and women from 18 to 60 years old. Cases (40): people with IBS according to the Rome IV criteria, and Controls (80): relatives without gastrointestinal disease. MAIN MEASUREMENTS: Sociodemographic variables, related stressful events, predominant evacuation patterns, and family repetition patterns for IBS. Data were analyzed with descriptive and inferential statistics. Chi-square for categorical data (< p.05 as significant) estimate of ORs with 95% confidence interval. The institutional ethics committee approved it. RESULTS: The IBS presentation pattern was repeated in relatives, mainly first-degree. The risk of suffering from IBS was higher when the father reported it (OR 11.2 (95% CI; 1.2 -100.1), than the mother OR 3,7 (95% CI; 1.4 - 9.9), sibling OR 2.8 (95% CI; 1.1 - 6.6. In both groups, the relative who most frequently presented IBS was in the collateral line (sibling) (37.5% in cases vs. 17.5% in controls (p=0.023). In both groups, the predominant gender was female, with 80. 0% in cases and 57.5% in controls. CONCLUSION: SII has a familial recurrence pattern in the Mexican population. The disease is more frequent in first-degree relatives. It is important to elucidate the importance of the role that plays genetic background vs. the influence of the family environment in SII.

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The ability to evade protection mechanisms and uncontrolled cell growth can lead to the development of mutations, whether somatic or germline, and consequently to the dreaded diagnosis of cancer. Breast cancer is considered the most common type of cancer in women in several regions of Brazil, mainly in the South and Southeast, second only to non-melanoma skin cancer. Approximately 5% to 10% of neoplasms are related to germline alterations that lead to hereditary predisposition. There is evidence of an association with mutations in nine genes, the highest risk being breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2). Due to its epidemiological importance, in this narrative review we observed the main genetic mutations and syndromes associated with breast carcinoma, the recommendations for screening in high-risk patients, and the indication for genetic counseling. Bibliographic research on the PubMed and Cochrane databases and analysis of the Guidelines Breast Cancer Risk Reduction and Breast Cancer Screening and Diagnosis, from June 2022 to September 2023. In this review, we observed a greater influence of germline mutations on breast cancer related to the genes BRCA1, BRCA2, PALB2, PTEN, CDH1, STK11 and, in Brazil, considered a country of ethnic-racial diversity, to TP53. As cancer screening in the country is opportunistic, knowledge of germline mutations associated with breast cancer offers specific screening recommendations for high-risk patients, indications for genetic counseling, and guidelines for prophylactic surgery, in addition to impacting the formulation of public screening policies. (AU)

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Background: To describe the indications and outcomes of BRCA mutation carriers undergoing nipple-sparing mastectomy (NSM). Methods: In this retrospective study, 76 BRCA mutation carriers with no cancer who opted to undergo risk reduction NSM or diagnosed with breast cancer (BC) who opted to undergo therapeutic NSM were included. Results: Indications for NSM: cancer treatment (n = 33), bilateral risk reduction (n = 39) and contralateral prophylactic NSM (n = 4). In a mean follow-up of 45 months (median: 30 months), one patient (2.5%) undergoing risk-reducing NSM developed a new BC. One (3%) local, one (3%) ipsilateral axillary and one (3%) distant recurrence were observed in BC patients. No partial or total nipple necrosis occurred. Conclusion: NSM is safe for reducing the risk of BC development in BRCA mutation carriers and for treating cancer.

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Colorectal cancer (CRC) is a major global health challenge and one of the top 10 cancers in Mexico. Lifestyle and genetic factors influence CRC development, prognosis, and therapeutic response; identifying risk factors, such as the genes involved, is critical to understanding its behavior, mechanisms, and prognosis. The association between KRAS gene variants (rs8720 and rs12587) and CRC in the Mexican population was analyzed. We performed in silico analysis and analyzed 310 healthy individuals and 385 CRC patients using TaqMan assays and real-time PCR. The CC and GG genotypes of rs8720 and rs12587 were identified as CRC risk factors (p < 0.05). The CC and TC genotypes of the rs8720 were associated with rectal cancer, age over 50 years, moderately differentiated histology, and advanced cancer stage. TG and GG genotypes of the rs12587 variant were a risk factor in the CRC group, in patients with stage I-II, males, and stage III-IV non-chemotherapy response. The TG haplotype is protected against CRC. The combined CCGG genotype was linked to CRC risk. In silico analysis revealed that the rs12587 and rs8720 variants could influence KRAS gene regulation via miRNAs. In conclusion, rs8720 and rs12587 variants of the KRAS gene were associated with CRC risk and could influence KRAS regulation via miRNAs.

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BACKGROUND: Sarcomas are a rare and diverse group of cancers occurring mainly in young individuals for which an underlying germline genetic cause remains unclear in most cases. METHODS: Germline DNA from 177 children, adolescents and young adults with soft tissue or bone sarcomas was tested using multigene panels with 113 or 126 cancer predisposing genes (CPGs) to describe the prevalence of germline pathogenic/likely pathogenic variants (GPVs). Subsequent testing of a subset of tumours for loss of heterozygosity (LOH) evaluation was performed to investigate the clinical and molecular significance of these variants. RESULTS: GPVs were detected in 21.5% (38/177) of the patients (15.8% in children and 21.6% in adolescents and young adults), with dominant CPGs being altered in 15.2% overall. These variants were found in genes previously associated with the risk of developing sarcomas (TP53, RB1, NF1, EXT1/2) but also in genes where that risk is still emerging/limited (ERCC2, TSC2 and BRCA2) or unknown (PALB2, RAD50, FANCM and others). The detection rates of GPVs varied from 0% to 33% across sarcoma subtypes and GPV carriers were more likely to present more than one primary tumour than non-carriers (21.1%×6.5%; p=0.012). Loss of the wild-type allele was detected in 48% of tumours from GPV carriers, mostly in genes definitively associated with sarcoma risk. CONCLUSION: Our findings reveal that a high proportion of young patients with sarcomas presented a GPV in a CPG, underscoring the urgency of establishing appropriate genetic screening strategies for these individuals and their families.

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The emergence of the rare syndrome called vaccine-induced immune thrombocytopenia and thrombosis (VITT) after adenoviral vector vaccines, including ChAdOx1 nCov-19, raises concern about one's predisposing risk factors. Here we report the case of a 56-year-old white man who developed VITT leading to death within 9 days of symptom onset. He presented with superior sagittal sinus thrombosis, right frontal intraparenchymal hematoma, frontoparietal subarachnoid and massive ventricular hemorrhage, and right lower extremity arterial and venous thrombosis. His laboratory results showed elevated D-dimer, C-reactive protein, tissue factor, P-selectin (CD62p), and positive anti-platelet factor 4. The patient's plasma promoted higher CD62p expression in healthy donors' platelets than the controls. Genetic investigation on coagulation, thrombophilia, inflammation, and type I interferon-related genes was performed. From rare variants in European or African genomic databases, 68 single-nucleotide polymorphisms (SNPs) in one allele and 11 in two alleles from common SNPs were found in the patient genome. This report highlights the possible relationship between VITT and genetic variants. Additional investigations regarding the genetic predisposition of VITT are needed.

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BACKGROUND: The behavior of anthropometrics and the relationship with genetic factors through a long-term perspective should be better explored. This study aims to verify the odds of maintaining the nutritional status classification after three years, according to the rs9939609 polymorphism (FTO gene). METHODS: It was a retrospective longitudinal study with 355 schoolchildren (7-17 years). Body mass index, body-fat percentage (BF%), and waist circumference (WC) were measured at baseline and follow-up. The FTO gene was evaluated from blood collection and genotyping performed by real-time polymerase chain reaction. Odds ratios and 95% confidence intervals were calculated. RESULTS: For those homozygous with the A allele, the odds of being at less favorable classification at follow-up were 2.29 (1.24; 4.22) and 4.05 (2.08; 7.86) times higher than expected for BF% and WC, respectively, whereas the odds of being in the more favorable classification at follow-up were 0.34 (0.12; 0.93) and 0.11 (0.01; 0.78) for BF% and WC, respectively. The odds of being at less favorable classification were higher for AA carriers with less favorable classification at baseline for BF% and WC compared to AT and TT carriers. CONCLUSIONS: Schoolchildren with a genetic predisposition to obesity and unfavorable anthropometric profile at baseline had more chances of maintaining their nutritional status after three years of follow-up.

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Pathogenic germline variants in the protection of telomeres 1 gene (POT1) have been associated with predisposition to a range of tumour types, including melanoma, glioma, leukaemia and cardiac angiosarcoma. We sequenced all coding exons of the POT1 gene in 2928 European-descent melanoma cases and 3298 controls, identifying 43 protein-changing genetic variants. We performed POT1-telomere binding assays for all missense and stop-gained variants, finding nine variants that impair or disrupt protein-telomere complex formation, and we further define the role of variants in the regulation of telomere length and complex formation through molecular dynamics simulations. We determine that POT1 coding variants are a minor contributor to melanoma burden in the general population, with only about 0.5% of melanoma cases carrying germline pathogenic variants in this gene, but should be screened in individuals with a strong family history of melanoma and/or multiple malignancies.

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ABSTRACT A total of 1.67 million breast cancer cases per year are reported worldwide. Of these, 5%-10% are caused by inherited mutations. Phenocopy is a rare phenomenon, with only a few cases reported in the literature. In phenocopies, phenotypes identical to those with genetic origin occur because of environmental factors rather than familial mutations. We describe a case of phenocopy in a 44-year-old female patient with triple-negative breast cancer. The mother and sister wee heterozygous for c.1813delA, p.Ile605TyrfsTer9 in BRCA2 . The patient underwent genetic testing for BRCA1 and BRCA2 and exome sequencing. Familial or other cancer variants were not detected. The most accepted phenocopy theory is that patients without genetic variants but who are carriers of these mutations undergo cellular changes due to environmental factors, increasing the risk of breast cancer. Therefore, the detection of phenocopy in patients with breast cancer is important in clinical practice.

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Abstract Kawasaki disease (KD) is an inflammatory condition that may affect genetically predisposed individuals in pediatric ages after infectious/environmental triggering. An infrequent finding associated with KD is ascending aortic aneurysm during or after the acute phase of the disease. In this Multimedia presentation, we describe a three-year-old girl submitted to surgical treatment.

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El síndrome de Dandy-Walker se asocia con dilatación quística del cuarto ventrículo, diversos grados de alteración del vérnix cerebeloso e hidrocefalia supratentorial. Se basa principalmente en un desarrollo anormal de las vías de comunicación del líquido cefalorraquídeo. Se ha sugerido predisposición genética asociada a malformaciones y alteraciones cromosómicas. El diagnóstico se puede llevar a cabo durante la etapa prenatal o posnatal, de forma clínica y estudios de diagnóstico por imagen. Se presenta el caso de una recién nacida que ingresó en la Unidad de Cuidados Intensivos Neonatales por presentar hipotonía, protrusión de la lengua con trastornos de la succión. Se le realizó ultrasonido transfontanelar, con dilatación de ventrículos laterales. Se apreció además de la dilatación de los ventrículos laterales, quiste en el plexo coroideo y signos de atrofia cerebral. Fue diagnosticada con el síndrome de Dandy-Walker, sin criterio quirúrgico, por no presentar signos de hidrocefalia. Se presenta el caso porque es una malformación poco frecuente del sistema nervioso central.

Dandy-Walker syndrome is associated with cystic dilatation of the fourth ventricle, varying degrees of abnormality of the cerebellar vermix, and supratentorial hydrocephalus. It is mainly based on an abnormal development of the cerebrospinal fluid communication pathways. Genetic predisposition associated with malformations and chromosomal alterations has been suggested. The diagnosis can be carried out during the prenatal or postnatal stage, clinically and diagnostic imaging studies. We present the case of a newborn who was admitted to the Neonatal Intensive Care Unit due to hypotonic, tongue protrusion with sucking disorders. A transfontanellar ultrasound was performed, with dilation of the lateral ventricles. In addition to the dilation of the lateral ventricles, a cyst in the choroid plexus and signs of brain atrophy were observed. She was diagnosed with Dandy-Walker syndrome, without surgical criteria because she did not present signs of hydrocephalus. The case is presented because it is a rare malformation of the central nervous system.

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Background: Fat Mass and Obesity-related (FTO) has been one of the genes consistently related to common obesity. Single nucleotide polymorphisms (SNPs) in FTO have been linked with the IRX3 gene. Aim: This study was designed by testing the hypothesis that: i) common SNPs in FTO and IRX3 are associated with obesity and related disorders; ii) there is significant linkage disequilibrium between both genes. Methods: A cross-sectional study was carried out on the Colombian Caribbean Coast. Anthropometric and biochemical variables were measured, and obesity and metabolic disorders were diagnosed. Four SNPs were genotyped: 3 at FTO locus (rs17817449, rs8050136, rs9939609) and one at IRX3 locus (rs3751723). LD between these SNPs was estimated. A logistic regression model was applied to estimate associations. Results: A total of 792 subjects were included. FTO and IRX3 were not in LD (D'≤ 0.03; R2≤ 0.03). TT genotype (rs9939609) was found to be associated with waist circumference (p= 0.04; adj-p= 0.01), and IRX3 SNP with Body Weight Excess (BWE) (OR= 1.06, adj-p= 0.03). One FTO-IRX3 haplotype was associated with BWE (G-A-A-T, rs17817449-rs8050136-rs9939609-rs3751723; OR= 0.67, p= 0.04). The statistical significance of these relations continued after admixture adjustment for a three-hybrid population (p= 0.03). Conclusions: FTO was related to waist circumference, and IRX3 was associated with BWE in Latin American adults. This relation remained statistically significant after an adjustment for sex, age, and genetic ancestry was performed. Despite that these genes were not in LD, findings of a haplotype involving FTO-IRX3 suggest a gene-gene interaction associated with an increased risk of BWE.

Introducción: FTO (Fat Mass and Obesity-related) se ha relacionado de manera consistente con la obesidad. Recientemente, Polimorfismos de Nucleótido Único (SNP) en este gen se han relacionado con el gen IRX3. Objetivo: Probar la hipótesis de que: i) SNPs en FTO e IRX3 están asociados con la obesidad y trastornos relacionados; ii) existe desequilibrio de ligamiento (LD) significativo entre ambos genes. Métodos: se realizó un estudio transversal en la costa caribe colombiana. Se valoraron variables antropométricas y bioquímicas, la obesidad y trastornos metabólicos. Se genotipificaron 4 SNPs: 3 en FTO (rs17817449, rs8050136, rs9939609) y uno en IRX3 (rs3751723). Se estimó el LD entre estos SNPs. Se aplicó un modelo de regresión logística para estimar asociaciones. Resultados: Se incluyeron 792 sujetos. FTO e IRX3 no se encontraron en LD (D' ≤0.03; R2 ≤0.03). El genotipo TT (rs9939609) se encontró asociado con la circunferencia de la cintura (p= 0.04; adj-p= 0.01), y el SNP IRX3 con el Exceso de Peso (EP) (OR= 1.06, adj-p= 0.03). Se encontró un haplotipo FTO-IRX3 asociado con EP (G-A-A-T, rs17817449-rs8050136-rs9939609-rs3751723; OR= 0.67, p= 0.04). Esta asociación persistió después del ajuste para una población mixta (p= 0.03). Conclusiones: FTO se encontró asociado con la circunferencia de la cintura e IRX3 con EP en adultos latinoamericanos. Estas asociaciones persistieron tras el ajuste por sexo, edad y ascendencia genética. Aunque estos genes no estaban en LD, los hallazgos de un haplotipo entre FTO-IRX3 sugieren una interacción gen-gen asociada con un mayor riesgo de EP.

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