Molecular Approach of Hereditary Arrhythmias, Long QT Syndrome, and Arrhythmogenic Right Ventricular Cardiomyopathy.

BACKGROUND: Hereditary cardiac arrhythmias result from mutations in various genes encoding ion channels. One major channelopathy is long QT syndrome, which has excel- lent genetic and clinical heterogeneity. Arrhythmogenic right ventricular cardiomyopa- thy, another hereditary arrhythmia type, also shows high genetic heterogeneity and variable expressivity. Next-generation sequencing is an effective tool to reveal the dis- ease's underlying genetic etiology. METHODS: In this study, we performed clinical exome sequencing or gene panel including cardiac arrhythmia and cardiomyopathy-associated genes by next-generation sequenc-ing in 13 unrelated patients. RESULTS: Five pathogenic or likely pathogenic mutations, including three novel mutations, were found in the total cases. CONCLUSION: This research shows a strong genetic heterogeneity in the disease. In addi- tion, the study revealed that patients with QT interval prolongation on electrocardio- gram might also have mutations in genes that are not associated with long QT syndrome, such as MYLK2 and DSG2. Therefore, our data helped expand the molecular scope of long QT syndrome. It is necessary to study with a broad perspective to elucidate the underly- ing molecular etiology in patients with hereditary cardiac arrhythmias.

New Perspectives on the Recurrent Monoallelic Germline Mutations of DNA Repair and Checkpoint Genes and Clinical Variability.

Background: Inherited cancers account for ∼10% of cancer cases. Many hereditary cancers are associated with mutations in DNA repair and checkpoint genes making their clinical surveillance important. Methods: We screened 900 patients using a comprehensive cancer gene panel with the following diagnoses: familial (n = 537, 59.6%), colorectal (n = 117, 13%), breast-ovarian (n = 215, 23.8%), endometrium (n = 12, 1.3%), gastric (n = 11, 1.2%), and thyroid (n = 8, 0.8%). Results: The most commonly mutated genes identified were ATM, MSH6, MUTYH, CHEK2, APC, MLH1, RAD50, PALB2, MSH2, CDH1, and PMS2. The most prevalent heterozygous was MUTYH: c.884C>T(P295L), which was predominant in the breast-ovarian group. Notably, the MUTYH, MSH6, and MSH2 variants showed a higher incidence of extracolonic malignancy. Among the DNA mismatch repair (MMR) genes, MSH6 mutations were the most common, followed by mutations in MLH1, MSH2, PMS2, and EPCAM. Conclusion: These findings offer a new perspective and suggest that, beyond ATM, CHEK2, and PALB2, patients with germline monoallelic mutations in MUTYH, MSH6, APC, CDH1, MHS2, and PMS2 may present with a hereditary breast-ovarian cancer phenotype. Continued developments in assessing and researching new variants of known cancer candidate genes will play an important role in improving individual risk prediction, therapy, and prognosis for familial cancers.

Liquid biopsy: Novel perspectives on the importance and spectrum of PIK3CA, PTEN and RET mutations in solid tumors.

Many people die from lung and breast cancer. Consequently, both physicians and researchers strive to provide reliable monitoring for disease, diagnosis and prognosis as well as resistance prediction. In the present study, a comprehensive liquid biopsy panel was performed on 474 patients to examine the importance and spectrum of recurrent somatic cancer mutations. Most patients visited the clinic with a diagnosis of advanced resistant cancer. The patients underwent a comprehensive liquid biopsy panel. Patients were divided into four groups based on cancer type as follows: Lung (n=379, 79.9%), breast (n=72, 15.2%), gastrointestinal (n=11, 2.3%) and other (n=12, 2.5%). Tier I-II-III classified variants were included in the study. The mean age was 60 years, with a range of 20-86 years. There were notably more male (n=272, 57.4%) than female patients (n=202, 42.6%). The most commonly mutated genes were TP53, EGFR, PIK3CA, RET, PTEN, MET, ATM and KRAS. The most common mutations were 'PIK3CA, c.3140A>G, p.His1047Arg', 'RET, c.2324delinsGAC, p.Glu775Glyfs*6', 'TP53, c.217G>C, p.Val73Leu', 'EGFR, c.2155G>A, p.Gly719Ser', 'PIK3CA, c.1624G>A, p.Glu542Lys', 'PTEN, c.397G>A, p.Val133Ile' and 'EGFR, c.2235_2249del, p.Glu746_Ala750del'. The PIK3CA, PTEN and RET variants showed a higher incidence in the breast and lung groups compared with other groups. To the best of our knowledge, the present study is the first to concentrate on PIK3CA, PTEN and RET mutations in the context of breast and lung adenocarcinoma and to evaluate both genetic variability and the effect of treatment. The present results showed that patients with solid tumors, particularly lung and breast cancer, may benefit from PIK3CA, PTEN and RET sequencing to assess clinical characteristics and prognosis. Discoveries regarding the gene structure and mechanisms of PIK3CA, PTEN and RET may inform more clinically meaningful therapeutic approaches for patients with cancer and serve an essential role in improving individual risk prediction, therapy and prognosis.

A novel BRCA1 duplication and new insights on the spectrum and frequency of germline large genomic rearrangements in BRCA1/BRCA2.

Heritable breast cancers account for 5% to 10% of all breast cancers, and monogenic, highly penetrant genes cause them. Around 90% of pathogenic variants in BRCA1 and BRCA2 are observed using gene sequencing, with another 10% identified through gene duplication/deletion analysis, which differs across various communities. In this study, we performed a next-generation sequencing panel and MLPA on 1484 patients to explain the importance of recurrent germline duplications/deletions of BRCA1-2 and their clinical results and determine how often BRCA gene LGRs were seen in people suspected of hereditary breast and ovarian cancer syndrome. The large genomic rearrangements (LGRs) frequency was approximately 1% (14/1484). All 14 mutations were heterozygous and detected in patients with breast cancer. BRCA1 mutations were more predominant (n = 8, 57.1%) than BRCA2 mutations (6, 42.9%). The most common recurrent mutations were BRCA2 exon three and BRCA1 exon 24 (23) deletions. To the best of our knowledge, BRCA1 5'UTR-exon11 duplication has never been reported before. Testing with MLPA is essential to identify patients at high risk. Our data demonstrate that BRCA1-2 LGRs should be considered when ordering genetic testing for individuals with a personal or family history of cancer, particularly breast cancer. Further research could shed light on BRCA1-2 LGRs' unique carcinogenesis roles.

Mutation spectrum of hereditary myopathies in Turkish patients and novel variants.

Hereditary myopathies are a heterogeneous disorder known to be associated with more than 100 genes. Although hereditary myopathy subgroups can be partially described with traditional methods such as muscle biopsy, next-generation sequencing (NGS) is essential to reveal the disease's underlying genetic etiology and molecular mechanisms. In this study, we performed clinical exome sequencing or whole-exome sequencing (CES/WES) in 20 unrelated Turkish patients. Thirteen pathogenic or likely pathogenic variants, including five novel variantswere detected in the 16 known hereditary myopathy genes. We achieved a high rate of diagnosis (65%) compared to previous studies. The most common condition noticed was limb-girdle muscular dystrophy (LGMD), which should not be ignored in patients diagnosed with myopathy. CES or WES provides a certain molecular diagnosis from a broad perspective to demonstrate underlying genetic causes in heterogeneous disorders. Therefore, exome sequencing offers a higher and more complete diagnosis than the gene panel.

Melanocortin 3 receptor gene polymorphism is associated with polycystic ovary syndrome in Turkish population.

Polycystic ovary syndrome (PCOS) is a frequent complex disorder with an ill-defined etiology. Genetic factors seem rather effective at the occurrence of the disease, however, the evidence of established various studies results are unsatisfied. We aimed to make a contribution to the genetic baseline of the disease by investigating melanocortin 3 receptor gene polymorphism in affected patients. 101 PCOS patients and 162 age-matched healthy volunteered control subjects recruited to the study. PCOS patients classified according to their BMI class and insulin resistance situation. Anthropometric measurements, physical examination results, laboratory findings, and hormone levels were recorded for each participant and analysis of two SNPs on the MC3R gene; rs3746619 and rs3827103 were performed. Although no significant difference was observed in rs3827103 polymorphism between PCOS patients and controls; rs3746619 polymorphism was determined associated with PCOS in the heritage of dominant (AA + AC) and co-dominant (AA) genotypes. Two polymorphisms did not found related to obesity and insulin resistance in PCOS subgroups analysis. MC3R gene rs 3746619 polymorphism was found associated with PCOS in the Turkish population and may make a contribution to the genetic baseline of the disease.