scholarly journals Comprehensive targeted next-generation sequencing in patients with slow-flow vascular malformations

2021 ◽  
Author(s):  
Akifumi Nozawa ◽  
Akihiro Fujino ◽  
Shunsuke Yuzuriha ◽  
Souichi Suenobu ◽  
Aiko Kato ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Signaling Pathway ◽  
Vascular Malformations ◽  
Pi3k Signaling ◽  
Slow Flow ◽  
Next Generation ◽  
Targeted Next Generation Sequencing ◽  
Pathogenic Variants ◽  
Pi3k Signaling Pathway ◽  
Generation Sequencing

Abstract Recent studies have shown that the PI3K signaling pathway plays an important role in the pathogenesis of slow-flow vascular malformations (SFVMs). Analysis of genetic mutations has advanced our understanding of the mechanisms involved in SFVM pathogenesis and may identify new therapeutic targets. We screened for somatic variants in a cohort of patients with SFVMs using targeted next-generation sequencing. Targeted next-generation sequencing of 29 candidate genes associated with vascular anomalies or with the PI3K signaling pathway was performed on affected tissues from patients with SFVMs. Fifty-nine patients with SFVMs (venous malformations n = 21, lymphatic malformations n = 27, lymphatic venous malformations n = 1, and Klippel–Trenaunay syndrome n = 10) were included in the study. TEK and PIK3CA were the most commonly mutated genes in the study. We detected eight TEK pathogenic variants in 10 samples (16.9%) and three PIK3CA pathogenic variants in 28 samples (47.5%). We also identified a pathogenic variant in RASA1 in one sample. In total, 38 of 59 patients (64.4%) with SFVMs harbored pathogenic variants in these three genes involved in the PI3K signaling pathway. Inhibitors of this pathway may prove useful as molecular targeted therapies for SFVMs.

Targeted next generation sequencing in patients with maturity-onset diabetes of the young (MODY)

2018 ◽  
Vol 31 (12) ◽  
pp. 1295-1304 ◽  
Author(s):  
Taha R. Özdemir ◽  
Özgür Kırbıyık ◽  
Bumin N. Dündar ◽  
Ayhan Abacı ◽  
Özge Ö. Kaya ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Maturity Onset Diabetes ◽  
Next Generation ◽  
Targeted Next Generation Sequencing ◽  
Pathogenic Variants ◽  
Onset Diabetes ◽  
Frequent Mutations ◽  
Standards And Guidelines ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Abstract Background Maturity-onset diabetes of the young (MODY) is a common form of monogenic diabetes. Fourteen genes have been identified, each leading to cause a different type of MODY. The aims of this study were to reveal both known and novel variants in MODY genes in patients with MODY using targeted next generation sequencing (NGS) and to present the genotype-phenotype correlations. Methods Mutation analysis of MODY genes (GCK, HNF1A, HNF4A, HNF1B, ABCC8, INS and KCNJ11) was performed using targeted NGS in 106 patients with a clinical diagnosis of MODY. The variants were evaluated according to American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines recommendations. Results A total of 18 (17%) variants were revealed among all patients. Seven variants in GCK, six in HNF4A, four in HNF1A and one in ABCC8 genes were found. Eight of them were previously published and 10 of them were assessed as novel pathogenic or likely pathogenic variants. Conclusions While the most frequent mutations are found in the HNF1A gene in the literature, most of the variants were found in the GCK gene in our patient group using the NGS method, which allows simultaneous analysis of multiple genes in a single panel.

Genetic study of pediatric hypertrophic cardiomyopathy in Egypt

2020 ◽  
Vol 30 (12) ◽  
pp. 1910-1916
Author(s):  
Rania K. Darwish ◽  
Alireza Haghighi ◽  
Zeinab S. Seliem ◽  
Sonia A. El-Saiedi ◽  
Nora H. Radwan ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Hypertrophic Cardiomyopathy ◽  
Genetic Background ◽  
Rare Variants ◽  
National Study ◽  
Next Generation ◽  
Targeted Next Generation Sequencing ◽  
Pathogenic Variants ◽  
Egyptian Children ◽  
Generation Sequencing

AbstractPaediatric cardiomyopathy is a progressive and often lethal disorder and the most common cause of heart failure in children. Despite their severe outcomes, their genetic etiology is still poorly characterised. The current study aimed at uncovering the genetic background of idiopathic primary hypertrophic cardiomyopathy in a cohort of Egyptian children using targeted next-generation sequencing. The study included 24 patients (15 males and 9 females) presented to the cardiomyopathy clinic of Cairo University Children’s Hospital with a median age of 2.75 (0.5–14) years. Consanguinity was positive in 62.5% of patients. A family history of hypertrophic cardiomyopathy was present in 20.8% of patients. Ten rare variants were detected in eight patients; two pathogenic variants (8.3%) in MBPC3 and MYH7, and eight variants of uncertain significance in MYBPC3, TTN, VCL, MYL2, CSRP3, and RBM20.Here, we report on the first national study in Egypt that analysed sarcomeric and non-sarcomeric variants in a cohort of idiopathic paediatric hypertrophic cardiomyopathy patients using next-generation sequencing. The current pilot study suggests that paediatric hypertrophic cardiomyopathy in Egypt might have a particular genetic background, especially with the high burden of consanguinity. Including the genetic testing in the routine diagnostic service is important for a better understanding of the pathophysiology of the disease, proper patient management, and at-risk detection. Genome-wide tests (whole exome/genome sequencing) might be better than the targeted sequencing approach to test primary hypertrophic cardiomyopathy patients in addition to its ability for the identification of novel genetic causes.

scholarly journals Germline Pathogenic Variants Identified by Targeted Next-Generation Sequencing of Susceptibility Genes in Pheochromocytoma and Paraganglioma

2021 ◽  
Vol 8 (1) ◽  
pp. 19-24
Author(s):  
Sinem Yalcintepe ◽  
Hakan Gurkan ◽  
Fatma Nur Korkmaz ◽  
Selma Demir ◽  
Engin Atli ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Susceptibility Genes ◽  
Next Generation ◽  
Clinical Genetic ◽  
Targeted Next Generation Sequencing ◽  
Clinical Genetic Testing ◽  
Pathogenic Variants ◽  
Diagnosis Rate ◽  
Gene Panels ◽  
Generation Sequencing

The aim of this study was to evaluate germline variant frequencies of pheochromocytoma and paraganglioma targeted susceptibility genes with next-generation sequencing method. Germline DNA from 75 cases were evaluated with targeted next-generation sequencing on an Illumina NextSeq550 instrument. KIF1B, RET, SDHB, SDHD, TMEM127, and VHL genes were included in the study, and Sanger sequencing was used for verifying the variants. The pathogenic/likely pathogenic variants were in the VHL, RET, SDHB, and SDHD genes, and the diagnosis rate was 24% in this study. Three different novel pathogenic variants were determined in five cases. This is the first study from Turkey, evaluating germline susceptibility genes of pheochromocytoma and paraganglioma with a detection rate of 24% and three novel variants. All patients with pheochromocytoma and paraganglioma need clinical genetic testing with expanded targeted gene panels for higher diagnosis rates.

Targeted Next-Generation Sequencing for Congenital Hypothyroidism With Positive Neonatal TSH Screening

2020 ◽  
Vol 105 (8) ◽  
pp. e2825-e2833 ◽  
Author(s):  
Takeshi Yamaguchi ◽  
Akie Nakamura ◽  
Kanako Nakayama ◽  
Nozomi Hishimura ◽  
Shuntaro Morikawa ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Congenital Hypothyroidism ◽  
Gene Dosage ◽  
Next Generation ◽  
Gene Dosage Effect ◽  
Targeted Next Generation Sequencing ◽  
Pathogenic Variants ◽  
Published Evidence ◽  
Unknown Significance ◽  
Generation Sequencing

Abstract Purpose Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder; however, its molecular etiology remains poorly understood. Methods We performed genetic analysis of 24 causative genes using next-generation sequencing in 167 CH cases, comprising 57 dyshormonogenesis (DH), 32 dysgenesis (TD) and 78 undiagnosed. The pathogenicity of variants was assessed by the American College of Medical Genetics guidelines, inheritance pattern, and published evidence. Furthermore, we compared the oligogenic groups and monogenic groups to examine the correlation between variant dosage and severity. Results We identified variants in 66.5% cases (111/167) and 15 genes, DUOX2, TSHR, PAX8, TG, TPO, DUOXA2, JAG1, GLIS3, DUOX1, IYD, SLC26A4, SLC5A5, SECISBP2, DIO1, and DIO3. Biallelic variants were identified in 12.6% (21/167), oligogenic in 18.0% (30/167), and monogenic in 35.9% (60/167); however, 68.5% of variants were classified as variant of unknown significance (VUS). Further examinations showed that 3 out of 32 cases with TD (9.4%) had pathogenic variants (2 of TSHR and 1 of TPO), and 8 out of 57 cases with DH (14.0%) (7 of DUOX2, 1 of TG) had pathogenic variants. In addition, TSH levels at the first visit were significantly higher in the oligogenic group than in the monogenic group. Conclusions The detection rate of pathogenic variants in Japanese CH was similar to that previously reported. Moreover, oligogenic cases were likely to be more severe than monogenic cases, suggesting that CH may exhibit a gene dosage effect. Further analysis of VUS pathogenicity is required to clarify the molecular basis of CH.

scholarly journals Targeted Next Generation Sequencing and Diagnosis of Congenital Hemolytic Anemias: A Three Years Experience Monocentric Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Elisa Fermo ◽  
Cristina Vercellati ◽  
Anna Paola Marcello ◽  
Ebru Yilmaz Keskin ◽  
Silverio Perrotta ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Blood Cell ◽  
Molecular Level ◽  
Patient Stratification ◽  
Next Generation ◽  
Rare Disorders ◽  
Targeted Next Generation Sequencing ◽  
Pathogenic Variants ◽  
Work Up ◽  
Generation Sequencing

Congenital hemolytic anemias (CHAs) are heterogeneous and rare disorders caused by alterations in structure, membrane transport, metabolism, or red blood cell production. The pathophysiology of these diseases, in particular the rarest, is often poorly understood, and easy-to-apply tools for diagnosis, clinical management, and patient stratification are still lacking. We report the 3-years monocentric experience with a 43 genes targeted Next Generation Sequencing (t-NGS) panel in diagnosis of CHAs; 122 patients from 105 unrelated families were investigated and the results compared with conventional laboratory pathway. Patients were divided in two groups: 1) cases diagnosed with hematologic investigations to be confirmed at molecular level, and 2) patients with unexplained anemia after extensive hematologic investigation. The overall sensitivity of t-NGS was 74 and 35% for families of groups 1 and 2, respectively. Inside this cohort of patients we identified 26 new pathogenic variants confirmed by functional evidence. The implementation of laboratory work-up with t-NGS increased the number of diagnoses in cases with unexplained anemia; cytoskeleton defects are well detected by conventional tools, deserving t-NGS to atypical cases; the diagnosis of Gardos channelopathy, some enzyme deficiencies, familial siterosterolemia, X-linked defects in females and other rare and ultra-rare diseases definitely benefits of t-NGS approaches.

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