Mutation Load of Multiple Ion Channel Gene Mutations in Brugada Syndrome

Cardiology ◽  
2017 ◽  
Vol 137 (4) ◽  
pp. 256-260 ◽  
Author(s):  
Francesca Gualandi ◽  
Fatima Zaraket ◽  
Michele Malagù ◽  
Giulia Parmeggiani ◽  
Cecilia Trabanelli ◽  
...  
Keyword(s):  
Brugada Syndrome ◽  
Genetic Diagnosis ◽  
Gene Mutations ◽  
Mutation Load ◽  
Pathogenic Variants ◽  
Digenic Inheritance ◽  
Double Heterozygosity ◽  
Death Cases ◽  
Generation Sequencing

Brugada syndrome is a primary arrhythmic syndrome that accounts for 20% of all sudden cardiac death cases in individuals with a structurally normal heart. Pathogenic variants associated with Brugada syndrome have been identified in over 19 genes, with SCN5A as a pivotal gene accounting for nearly 30% of cases. In contrast to other arrhythmogenic channelopathies (such as long QT syndrome), digenic inheritance has never been reported in Brugada syndrome. Exploring 66 cardiac genes using a new custom next-generation sequencing panel, we identified a double heterozygosity for pathogenic mutations in SCN5A and TRPM4 in a Brugada syndrome patient. The parents were heterozygous for each variation. This novel finding highlights the role of mutation load in Brugada syndrome and strongly suggests the adoption of a gene panel to obtain an accurate genetic diagnosis, which is mandatory for risk stratification, prevention, and therapy.

299 The prevalence and role of SCN10A variants in Han Chinese patients with Brugada syndrome: the SADS-TW BrS registry

2020 ◽  
Vol 41 (Supplement_1) ◽  
Author(s):  
C-Y Chen ◽  
Y-B Liu ◽  
T-P Lu ◽  
Q-Y Yu ◽  
L-Y Lin ◽  
...  
Keyword(s):  
Brugada Syndrome ◽  
Rare Variants ◽  
Han Chinese ◽  
Chinese Patients ◽  
P Value ◽  
Common Variants ◽  
Pathogenic Variants ◽  
In Silico Analyses ◽  
Generation Sequencing

Abstract On Behalf SADS-TW BrS registry Background Brugada syndrome (BrS) is an inheritable arrhythmic disease responsible for sudden cardiac death. Information on the prevalence and role of SCN10A variants in BrS is limited and equivocal. Purpose We aimed to investigate the prevalence and role of SCN10A variants in BrS in Han Chinese. Methods From 2000 to 2017, we prospectively and consecutively enrolled 176 unrelated BrS patients from the Han Chinese population in Taiwan (the SADS-TW BrS registry). Thirty-four BrS-related genes were screened by next-generation sequencing, using Taiwan Biobank as the population reference. The pathogenicity was evaluated by literature review and in silico analyses, including the SKAT-O algorithm. Results The SKAT-O algorithm showed that rare variants of SCN10A, but not common variants, were significantly different between BrS patients and healthy controls in the additive and dominant models (p-value <0.001), suggesting that rare SCN10A variants may play a role in BrS. Six likely pathogenic SCN10A variants were found in 6 patients and were compared to 25 pathogenic or likely pathogenic SCN5A variants found in 29 patients. The patients with likely pathogenic SCN10A variants tended to exhibit sudden death in older age and have a shorter QRS interval than those carrying pathogenic or likely pathogenic SCN5A variants or no variants in either gene (p = 0.06, 0.07, respectively). Collectively, the prevalence of likely pathogenic SCN10A variants was 3.4% in Han Chinese patients with BrS in Taiwan. Conclusions SCN10A likely pathogenic variants were present in 3.4% of Han Chinese BrS patients. Rare SCN10A variants may play a role in BrS, and may have impact on clinical and electrocardiographic manifestations. Table 1. Patient Nucleotide Amino acid TWB gnomAD_EA REVEL CADD PHRED SIFT Polyphen-2 GERP++ 1 c.5789A > T p.D1930V 0.001318 0.0008700 0.479 24.5 Damaging Possibly damaging 4.22 2 c.2341G > A p.G781R 0 0.00005301 0.866 33 Damaging Probably damaging 4.83 3 c.5587C > T p.R1863W 0.000502 0 0.832 27.8 Damaging Probably damaging 1.97 4 c.2161C > T p.P721S 0.000989 0.0009016 0.933 28.5 Damaging Probably damaging 4.19 5 c.3749G > A p.R1250Q 0 0 0.907 31 Damaging Probably damaging 4.23 6 c.1825A > T p.R609W 0.000659 0.0001591 0.811 32 Damaging Probably damaging 4.28 Clinical and predicted functional characteristics of 6 likely pathogenic SCN10A variants. EA = East Asian; GERP = Genomic Evolutionary Rate Profiling; TWB = Taiwan Biobank. Transcript: NM_006514.3. Abstract 299 Figure. Location of the SCN10A variants

scholarly journals Genetic Causes of Oculocutaneous Albinism in Pakistani Population

Genes ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 492
Author(s):  
Zureesha Sajid ◽  
Sairah Yousaf ◽  
Yar M. Waryah ◽  
Tauqeer A. Mughal ◽  
Tasleem Kausar ◽  
...  
Keyword(s):  
Genetic Interaction ◽  
Genetic Diagnosis ◽  
Underlying Disease ◽  
Oculocutaneous Albinism ◽  
Disease Etiology ◽  
Locus Heterogeneity ◽  
Pathogenic Variants ◽  
Digenic Inheritance ◽  
Inbred Populations ◽  
Pathological Variant

Melanin pigment helps protect our body from broad wavelength solar radiation and skin cancer. Among other pigmentation disorders in humans, albinism is reported to manifest in both syndromic and nonsyndromic forms as well as with varying inheritance patterns. Oculocutaneous albinism (OCA), an autosomal recessive nonsyndromic form of albinism, presents as partial to complete loss of melanin in the skin, hair, and iris. OCA has been known to be caused by pathogenic variants in seven different genes, so far, according to all the currently published population studies. However, the detection rate of alleles causing OCA varies from 50% to 90%. One of the significant challenges of uncovering the pathological variant underlying disease etiology is inter- and intra-familial locus heterogeneity. This problem is especially pertinent in highly inbred populations. As examples of such familial locus heterogeneity, we present nine consanguineous Pakistani families with segregating OCA due to variants in one or two different known albinism-associated genes. All of the identified variants are predicted to be pathogenic, which was corroborated by several in silico algorithms and association with diverse clinical phenotypes. We report an individual affected with OCA carries heterozygous, likely pathogenic variants in TYR and OCA2, raising the question of a possible digenic inheritance. Altogether, our study highlights the significance of exome sequencing for the complete genetic diagnosis of inbred families and provides the ramifications of potential genetic interaction and digenic inheritance of variants in the TYR and OCA2 genes.

scholarly journals Geographical Variation in the profile of RET Variants in Patients with Medullary Thyroid Cancer: A Comprehensive Review

2021 ◽  
Author(s):  
Rui M. B. Maciel ◽  
Ana Luiza Maia
Keyword(s):  
Haplotype Analysis ◽  
Medullary Thyroid Cancer ◽  
Genetic Diagnosis ◽  
Epidemiological Data ◽  
Global Perspective ◽  
Causative Role ◽  
Medullary Thyroid ◽  
Pathogenic Variants

Genetic variability in humans is influenced by many factors, such as natural selection, mutations, genetic drift, and migrations. Molecular epidemiology evaluates the contribution of genetic risk factors in the etiology, diagnosis, and prevention of a particular disease. Few areas of medicine have been so clearly affected by genetic diagnosis and management as multiple neoplasia type 2 (MEN2), in which activating pathogenic variants in the RET gene results in the development of medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism in nearly 98%, 50% and 25% of gene carriers, respectively. Here, we aimed to collect RET genotyping data worldwide to analyze the distribution and frequency of RET variants from a global perspective. We show that the mutational spectrum of RET is observed worldwide. The codon 634 variants seem to be the most prevalent, but there are differences in the type of amino acid exchanges among countries and in the frequencies of the other RET codon variants. Most interestingly, studies using haplotype analysis or pedigree linkage have demonstrated that some pathogenic RET variants have been transmitted to offspring for centuries, explaining some local prevalence due to a founder effect. Unfortunately, after almost three decades after the causative role of the germline RET variants have been reported in hereditary MTC, comprehensive genotyping data remain limited to a few countries. The heterogeneity of RET variants justifies the need for a global effort to describe epidemiological data of families with MEN2 to further understand the genetic background and environmental circumstances that affect disease presentation.

scholarly journals Genetic analyses of the NF1 gene in Turkish neurofibromatosis type I patients and definition of three novel variants

2017 ◽  
Vol 20 (1) ◽  
pp. 13-20 ◽  
Author(s):  
SD Ulusal ◽  
H Gürkan ◽  
E Atlı ◽  
SA Özal ◽  
M Çiftdemir ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Genetic Diagnosis ◽  
Neurofibromatosis Type ◽  
Type I ◽  
Neurofibromatosis Type I ◽  
Next Generation ◽  
Loss Of Function ◽  
Pathogenic Variants ◽  
Nf1 Gene ◽  
Generation Sequencing

Abstract Neurofibromatosis Type I (NF1) is a multi systemic autosomal dominant neurocutaneous disorder predisposing patients to have benign and/or malignant lesions predominantly of the skin, nervous system and bone. Loss of function mutations or deletions of the NF1 gene is responsible for NF1 disease. Involvement of various pathogenic variants, the size of the gene and presence of pseudogenes makes it difficult to analyze. We aimed to report the results of 2 years of multiplex ligation-dependent probe amplification (MLPA) and next generation sequencing (NGS) for genetic diagnosis of NF1 applied at our genetic diagnosis center. The MLPA, semiconductor sequencing and Sanger sequencing were performed in genomic DNA samples from 24 unrelated patients and their affected family members referred to our center suspected of having NF1. In total, three novel and 12 known pathogenic variants and a whole gene deletion were determined. We suggest that next generation sequencing is a practical tool for genetic analysis of NF1. Deletion/duplication analysis with MLPA may also be helpful for patients clinically diagnosed to carry NF1 but do not have a detectable mutation in NGS.

scholarly journals Recurrent Synovitis of Hip and MEFV Gene Related Arthritis in Children

2020 ◽  
Author(s):  
Farhad Salehzadeh ◽  
Mehrdad Mirzarahimi
Keyword(s):  
Rheumatic Disease ◽  
Peripheral Blood ◽  
Mefv Gene ◽  
Gene Mutations ◽  
Mediterranean Area ◽  
Hip Joints ◽  
Mefv Mutations ◽  
Pathogenic Variants ◽  
Pathologic Findings

Abstract Background : Recurrent and relapsing arthritis has been proposed to describe a group of arthritis with recurring and periodic nature, in which the joints are intermittently involved. This study reports three non-FMF patients with heterozygous MEFV gene mutations and an extraordinary arthritis as a recurrent synovitis of hip (RSH) Methods : During 16-years from 2003 to 2019 at pediatric rheumatologic clinic among 195 recorded files with chronic oligoarthritis, 3 patients with diagnosis of recurrent synovitis of hip (RSH) were reviewed thoroughly. Peripheral blood was collected from patients and the samples were screened for the 12 common MEFV gene pathogenic variants. Results: This study included three patients, two female and one male with relapsing idiopathic arthritis that has been located on hip joints as a sole manifestation and pathologic findings of MEFV mutations as follow: A744S, V726A, and R761H. Conclusion : On the basis of possible role of MEFV gene in different rheumatic disease, MEFV gene related arthritis may be considered as a background of RSH particularly in Mediterranean area.

scholarly journals Updating the Genetic Landscape of Inherited Retinal Dystrophies

2021 ◽  
Vol 9 ◽  
Author(s):  
Belén García Bohórquez ◽  
Elena Aller ◽  
Ana Rodríguez Muñoz ◽  
Teresa Jaijo ◽  
Gema García García ◽  
...  
Keyword(s):  
Genetic Diagnosis ◽  
Diagnostic Process ◽  
Reproductive Decisions ◽  
Inherited Retinal Dystrophies ◽  
Pathogenic Variants ◽  
Retinal Dystrophies ◽  
Genetic Landscape ◽  
Custom Panel ◽  
Generation Sequencing ◽  
Autosomal Recessive Pattern

Inherited retinal dystrophies (IRD) are a group of diseases characterized by the loss or dysfunction of photoreceptors and a high genetic and clinical heterogeneity. Currently, over 270 genes have been associated with IRD which makes genetic diagnosis very difficult. The recent advent of next generation sequencing has greatly facilitated the diagnostic process, enabling to provide the patients with accurate genetic counseling in some cases. We studied 92 patients who were clinically diagnosed with IRD with two different custom panels. In total, we resolved 53 patients (57.6%); in 12 patients (13%), we found only one mutation in a gene with a known autosomal recessive pattern of inheritance; and 27 patients (29.3%) remained unsolved. We identified 120 pathogenic or likely pathogenic variants; 30 of them were novel. Among the cone-rod dystrophy patients, ABCA4 was the most common mutated gene, meanwhile, USH2A was the most prevalent among the retinitis pigmentosa patients. Interestingly, 10 families carried pathogenic variants in more than one IRD gene, and we identified two deep-intronic variants previously described as pathogenic in ABCA4 and CEP290. In conclusion, the IRD study through custom panel sequencing demonstrates its efficacy for genetic diagnosis, as well as the importance of including deep-intronic regions in their design. This genetic diagnosis will allow patients to make accurate reproductive decisions, enroll in gene-based clinical trials, and benefit from future gene-based treatments.

scholarly journals The Potential Role of Aldosterone-Producing Cell Clusters in Adrenal Disease

2020 ◽  
Vol 52 (06) ◽  
pp. 427-434
Author(s):  
Jung Soo Lim ◽  
William E. Rainey
Keyword(s):  
Gene Mutations ◽  
Normal Subjects ◽  
Secondary Hypertension ◽  
Cell Clusters ◽  
Somatic Gene ◽  
Aldosterone Production ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing ◽  
Made In

AbstractPrimary aldosteronism (PA) is the most common cause of secondary hypertension. The hallmark of PA is adrenal production of aldosterone under suppressed renin conditions. PA subtypes include adrenal unilateral and bilateral hyperaldosteronism. Considerable progress has been made in defining the role for somatic gene mutations in aldosterone-producing adenomas (APA) as the primary cause of unilateral PA. This includes the use of next-generation sequencing (NGS) to define recurrent somatic mutations in APA that disrupt calcium signaling, increase aldosterone synthase (CYP11B2) expression, and aldosterone production. The use of CYP11B2 immunohistochemistry on adrenal glands from normal subjects, patients with unilateral and bilateral PA has allowed the identification of CYP11B2-positive cell foci, termed aldosterone-producing cell clusters (APCC). APCC lie beneath the adrenal capsule and like APA, many APCC harbor somatic gene mutations known to increase aldosterone production. These findings suggest that APCC may play a role in pathologic progression of PA. Herein, we provide an update on recent research directed at characterizing APCC and also discuss the unanswered questions related to the role of APCC in PA.

scholarly journals Detection of Folliculin Gene Mutations in Two Chinese Families with Birt-Hogg-Dube Syndrome

2017 ◽  
Vol 2017 ◽  
pp. 1-6 ◽  
Author(s):  
Lv Liu ◽  
Kai Yang ◽  
Xiang Wang ◽  
Zhihui Shi ◽  
Yifeng Yang ◽  
...  
Keyword(s):  
Direct Sequencing ◽  
Mrna Level ◽  
Genetic Diagnosis ◽  
Gene Mutations ◽  
Renal Cysts ◽  
Insertion Mutation ◽  
Chinese Families ◽  
Increased Risk ◽  
Pulmonary Cysts

Birt-Hogg-Dube syndrome (BHD, OMIM#135150) is a rare disease in clinic; it is characterized by skin fibrofolliculomas, pulmonary cysts with an increased risk of recurrent pneumothorax, renal cysts, and renal neoplasms. Previous studies have demonstrated that variants in folliculin (FLCN, NM_144997) are mainly responsible for this disease. In this research, we enrolled two BHD families and applied direct sequencing of FLCN to explore the genetic lesions in them. Two FLCN mutations were identified: one is a novel deletion variant (c.668delA/p.N223TfsX19), while the other is a previously reported insertion mutation (c.1579_1580insA/p.R527QfsX75). And the pathogenicity of both variants was confirmed by cosegregation assay. Bioinformatics analysis showed that c.668delA may lead to functional haploinsufficiency of FLCN because mRNA carrying this mutation exhibits a faster degradation rate comparing to the wild type. Real-time qPCR also confirmed that the mRNA level of FLCN expression in the proband was decreased significantly compared with the controls, which may disrupt the mTOR pathway and lead to BHD. The insertion mutation (c.1579_1580insA) was predicted to cause a prolonged amino acid sequence of FLCN. The present identification of two mutations not only further supports the important role of tumor suppressor FLCN in BHD and primary spontaneous pneumothorax, but also expands the spectrum of FLCN mutations and will provide insight into genetic diagnosis and counseling of families with BHD.

scholarly journals Phenotypic and Genotypic Characterization of NPRL2-Related Epilepsy: Two Case Reports and Literature Review

2021 ◽  
Vol 12 ◽  
Author(s):  
Yulin Sun ◽  
Lin Wan ◽  
Huimin Yan ◽  
Zhichao Li ◽  
Guang Yang
Keyword(s):  
Literature Review ◽  
Frameshift Mutation ◽  
Focal Epilepsy ◽  
Case Reports ◽  
Clinical Manifestations ◽  
Gene Mutations ◽  
Pathogenic Variants ◽  
Treatment Processes ◽  
Generation Sequencing

The phenotype of nitrogen permease regulator-like 2 (NPRL2) gene-related epilepsy clinically manifests as a range of epilepsy syndromes, including familial focal epilepsy with variable foci (FFEVF), sleep-related hypermotor epilepsy (SHE), temporal lobe epilepsy (TLE), frontal lobe epilepsy (FLE), and infantile spasms (IS). The association between phenotype and genotype of NPRL2 variants has not been widely explored. This study aimed to explore the phenotype and genotype spectrum of NPRL2-related epilepsy. Here, we presented two clinical cases with NPRL2-related epilepsy, and discussed the characteristics, diagnosis, and treatment processes in the context of existing literature. Two novel NPRL2 likely pathogenic variants were identified by next-generation sequencing, including one splicing mutation (c.933-1G>A), and one frameshift mutation (c.257delG). The results of literature review showed that there were a total of 20 patients with NPRL2-related epilepsy whose mutations were mostly missense and hereditary. These findings indicate that the possibility of NPRL2 gene mutations in focal epilepsy should be considered for patients with family history, and that patients carrying different NPRL2 variants have different clinical manifestations. Our study expanded the genotype spectrum of NPRL2 and suggested that the type of NPRL2 variants might provide important information for the prognosis evaluation.

Role of CACNA1C variants in Brugada syndrome: clinical aspects and genetic testing strategies

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
V Novelli ◽  
M Memmi ◽  
A Malovini ◽  
A Mazzanti ◽  
N Liu ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Brugada Syndrome ◽  
Genetic Variants ◽  
Clinical Aspects ◽  
Functional Evaluation ◽  
Discovery Cohort ◽  
Functional Studies ◽  
Pathogenic Variants ◽  
The Impact

Abstract Background Inconsistent data support the role of CACNA1C as a disease-causing gene responsible for Brugada syndrome (BrS). As of today, the only gene consistently linked with BrS is SCN5A. Several CACNA1c genetic variants have been reported in association wirh BrS; however, due to the limited evidence, CACNA1C is not suggested for routine genetic screening for BrS. Purpose In this study, we carried out a systematic screening of CACNA1C gene, including a functional evaluation of the identified variants, in order to determine the yield of screening in a large series of BrS probands and to address the hypothesis that an appropriate clinical selection of patients would substantially improve the yield of genetic testing. Methods and results Overall 564 consecutive patients, referred for BrS genetic testing, were sequenced for CACNA1C gene. Patients were divided in two groups: discovery cohort (n=200 patients) and confirmation cohort (n=363 patients). Furthermore, analysis of the clinical phenotypes of a matched SCN5A positive BrS cohort (n=146) was included for phenotype characterization. In the discovery cohort we identified 11 different genetic variants of whom 2 (18%) were considered as potentially causative based on ACMG guidelines. However, a large proportion (81%) was classified as variants of unknown significance (VUS). Functional evaluation of the identified variants, including pathogenic and VUS, was assessed by patch-clamp and immunofluorescence studies. Re-evaluation of the variants, including functional studies results, indicated an increase of pathogenic or likely pathogenic variants (81%) getting a yield of screening of 5% in the discovery cohort. Results from the confirmation cohort confirmed a low rate of CACNA1C carriers with a yield of screening of 2.2%. Analysing the clinical phenotype of all CACNA1C carriers showed a significantly shorter QTc [371 ms ± 16 ms vs. 399±18 ms; p=0.000004]. Furthermore, the prevalence of CACNA1C variants was highest (12.9%) among patients with a QTc in the lowest quartile (QTc <390 ms). ROC curve showed an AUC of 0.91 for QTc a cut-off of 385 ms, suggesting a high predictive accuracy. Conclusion We confirmed that CACNA1C variants are not a common cause of BrS, with a yield of screening of 2–5%. However, pathogenic variants are more frequent (12.5%) in patients with a shorter QTc, suggesting a genetic testing strategy in this subgroup of BrS patients. Furthermore, our data highlights the impact of robust functional studies to improve variant classification and reduce uncertainties. Funding Acknowledgement Type of funding source: None

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