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Germline pathogenic variants in the DNA mismatch repair genes (MMR): MLH1, MSH2, MSH6, and PMS2, are causative of Lynch syndrome (LS). However, many of the variants mapping outside the invariant splice site positions (IVS ± 1, IVS ± 2) are classified as variants of unknown significance (VUS). Three such variants (MLH1 c.588+5G>C, c.588+5G>T and c.677+5G>A) were identified in 8 unrelated LS families from Argentina, Brazil and Chile. Herein, we collected clinical information on these families and performed segregation analysis and RNA splicing studies to assess the implication of these VUS in LS etiology. Pedigrees showed a clear pattern of variant co-segregation with colorectal cancer and/or other LS-associated malignancies. Tumors presented deficient expression of MLH1-PMS2 proteins in 7/7 of the LS families, and MSI-high status in 3/3 cases. Moreover, RNA analyses revealed that c.588+5G>C and c.588+5G>T induce skipping of exon 7 whereas c.677+5G>A causes skipping of exon 8. In sum, we report that the combined clinical findings in the families and the molecular studies provided the evidences needed to demonstrate that the three MLH1 variants are causative of LS and to classify c.588+5G>C and c.677+5G>A as class 5 (pathogenic), and c.588+5G>T as class 4 (likely-pathogenic). Our findings underline the importance of performing clinical and family analyses, as well as RNA splicing assays in order to determine the clinical significance of intronic variants, and contribute to the genetic counseling and clinical management of patients and their relatives.

Background: Congenital heart diseases are the most common type of congenital defects, and account for more deaths in the first year of life than any other condition, when infectious etiologies are ruled out., Objectives: To evaluate survival, and to identify risk factors in deaths in newborns with critical and/or complex congenital heart disease in the neonatal period., Methods: A cohort study, nested to a randomized case-control, was performed, considering the Confidence Interval of 95% (95% CI) and significance level of 5%, paired by gender of the newborn and maternal age. Case-finding, interviews, medical record analysis, clinical evaluation of pulse oximetry (heart test) and Doppler echocardiogram were performed, as well as survival analysis, and identification of death-related risk factors., Results: The risk factors found were newborns younger than 37 weeks (Relative Risk - RR: 2.89; 95% CI [1.49-5.56]; p = 0.0015), weight of less than 2,500 grams (RR: 2.33 [; 95% CI 1.26-4.29]; p = 0.0068), occurrence of twinning (RR: 11.96 [95% CI 1.43-99.85]; p = 0.022) and presence of comorbidity (RR: 2.27 [95% CI 1.58-3.26]; p < 0.0001). The incidence rate of mortality from congenital heart disease was 81 cases per 100,000 live births. The lethality attributed to critical congenital heart diseases was 64.7%, with proportional mortality of 12.0%. The survival rate at 28 days of life decreased by almost 70% in newborns with congenital heart disease. The main cause of death was cardiogenic shock., Conclusion: Preterm infants with low birth weight and comorbidities presented a higher risk of mortality related to congenital heart diseases. This cohort was extinguished very quickly, signaling the need for greater investment in assistance technology in populations with this profile.

Approximately 5-10% of breast cancers are caused by germline mutations in high penetrance predisposition genes. Among these, BRCA1 and BRCA2, which are associated with the Hereditary Breast and Ovarian Cancer (HBOC) syndrome, are the most frequently affected genes. Recent studies confirm that gene rearrangements, especially in BRCA1, are responsible for a significant proportion of mutations in certain populations. In this study we determined the prevalence of BRCA rearrangements in 145 unrelated Brazilian individuals at risk for HBOC syndrome who had not been previously tested for BRCA mutations. Using Multiplex Ligation-dependent Probe Amplification (MLPA) and a specific PCR-based protocol to identify a Portuguese founder BRCA2 mutation, we identified two (1,4%) individuals with germline BRCA1 rearrangements (c.547+240&#95;5193+178del and c.4675+467&#95;5075-990del) and three probands with the c.156&#95;157insAlu founder BRCA2 rearrangement. Furthermore, two families with false positive MLPA results were shown to carry a deleterious point mutation at the probe binding site. This study comprises the largest Brazilian series of HBOC families tested for BRCA1 and BRCA2 rearrangements to date and includes patients from three regions of the country. The overall observed rearrangement frequency of 3.44% indicates that rearrangements are relatively uncommon in the admixed population of Brazil.

Aim: To study the association between genetic ancestry, non-alcoholic fatty liver disease (NAFLD) metabolic characteristics in two cohorts of patients, from Brazil and Portugal., Methods: We included 131 subjects from Brazil [(n = 45 with simple steatosis (S. Steatosis) and n = 86 with nonalcoholic steatohepatitis (NASH)] and 90 patients from Portugal (n = 66, S. Steatosis; n = 24, NASH). All patients had biopsy-proven NAFLD. In histologic evaluation NAFLD activity score was used to assess histology and more than 5 points defined NASH in this study. Patients were divided into two groups according to histology diagnosis: simple steatosis or non-alcoholic statohepatitis. Genetic ancestry was assessed using real-time polymerase chain reaction. Seven ancestry informative markers (AT3-I/D, LPL, Sb19.3, APO, FY-Null, PV92, and CKMM) with the greatest ethnic-geographical differential frequencies (≥ 48%) were used to define genetic ancestry. Data were analyzed using R PROJECTS software. Ancestry allele frequencies between groups were analyzed by GENEPOP online and the estimation of genetic ancestry contribution was evaluated by ADMIX-95 software. The 5% alpha-error was considered as significant (P < 0.05)., Results: In the Brazilian sample, NASH was significantly more frequent among the elderly patients with diabetes (NASH 56 ± 1.1 years old vs S. Steatosis 51 ± 1.5 years old, P = 3.7 x 10(-9)), dyslipidemia (NASH 63% vs S. Steatosis 37%, P = 0.009), higher fasting glucose levels (NASH 124 ± 5.2 vs S. Steatosis 106 ± 5.3, P = 0.001) and Homeostatic Model of Assessment index > 2.5 [NASH 5.3 (70.8%) vs S. Steatosis 4.6 (29.2%) P = 0.04]. In the Portuguese study population, dyslipidemia was present in all patients with NASH (P = 0.03) and hypertension was present in a larger percentage of subjects in the S. Steatosis group (P = 0.003, respectively). The genetic ancestry contribution among Brazilian and Portuguese individuals with NASH was similar to those with S. Steatosis from each cohort (Brazilian cohort: P = 0.75; Portuguese cohort: P = 0.97). Nonetheless, the genetic ancestry contribution of the Brazilian and Portuguese population were different, and a greater European and Amerindian ancestry contribution was detected in the Portuguese population while a higher African genetic ancestry contribution was observed in Brazilian population of both NASH and S. Steatosis groups., Conclusion: There was no difference between the genetic ancestry contribution among Brazilian and Portuguese individuals with NASH and S. Steatosis from each cohort.

Syringomas are benign adnexal tumors derived from the intraepidermal portion of eccrine sweat ducts. Clinically, they usually appear as small yellow or skin-colored papules ranging from 1-3 mm in diameter on the lower eyelids. The condition of eruptive syringomas is a clinically distinct, uncommon variant of syringomas. This entity was first recognized by Darier and Jacquet in 1887. Since the initial description, less than 100 cases have been reported to date. Although eruptive syringomas can develop on various sites of the body, instances of widespread involvement, known as generalized eruptive syringoma, are rare. In this paper, we present a case of generalized eruptive syringoma on a 26-year-woman. She exhibited multiple, eruptive asymptomatic papules, symmetrically distributed on the face, scalp, upper and lower extremities, chest, and abdomen.