scholarly journals Identification of NID1 as a novel candidate susceptibility gene for familial non-medullary thyroid carcinoma using whole exome sequencing

2021 ◽  
Author(s):  
Luis Eduardo Barbalho de Mello ◽  
Thaise Nayane Ribeiro Carneiro ◽  
Aline Neves Araujo ◽  
Camila Xavier Alves ◽  
Pedro Alexandre Favoretto Galante ◽  
...  
Keyword(s):  
Thyroid Carcinoma ◽  
Exome Sequencing ◽  
Medullary Thyroid Carcinoma ◽  
Whole Exome Sequencing ◽  
Susceptibility Gene ◽  
Thyroid Tissue ◽  
Family Members ◽  
Susceptibility Genes ◽  
Medullary Thyroid ◽  
Whole Exome

The genetics underlying non-syndromic familial non-medullary thyroid carcinoma (FNMTC) is still poorly understood. To identify susceptibility genes for FNMTC, we performed whole exome sequencing (WES) in a Brazilian family affected by papillary thyroid carcinoma (PTC) in three consecutive generations. WES was performed in four affected and two unaffected family members. Manual inspection in over 100 previously reported susceptibility genes for FNMTC showed that no variants in known genes co-segregated with disease phenotype in this family. Novel candidate genes were investigated using PhenoDB and filtered using Genome Aggregation (gnomAD) and Online Archive of Brazilian Mutations (ABraOM) population databases. The missense variant p.Ile657Met in the NID1 gene was the only variant that co-segregated with the disease, while absent in unaffected family members and controls. The allele frequency for this variant was <0.0001 in the gnomAD and ABbraOM databases. In silico analysis predicted the variant to be deleterious or likely damaging to the protein function. Somatic mutations in NID1 gene were found in nearly 500 cases of different cancer subtypes in the intOGen platform. Immunohistochemistry analysis showed NID1 expression in PTC cells, while it was absent in normal thyroid tissue. Our findings were corroborated using data from the TCGA cohort. Moreover, higher expression of NID1 was associated with higher likelihood of relapse after treatment and N1b disease in PTCs from the TCGA cohort. Although replication studies are needed to better understand the role of this variant in the FNMTC susceptibility, the NID1 variant (c.1971T>G) identified in this study fulfills several criteria that suggest it as a new FNMTC predisposing gene.

Abstract 15841: Whole Exome Sequencing and Analysis for Sudden Unexplained Death in the Young: A Case Series

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Nupoor Narula ◽  
David J Tester ◽  
Anna Paulmichl ◽  
Joseph J Maleszewski ◽  
Michael J Ackerman
Keyword(s):  
Sudden Death ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Effective Means ◽  
Susceptibility Gene ◽  
Case Series ◽  
Susceptibility Genes ◽  
Sudden Unexplained Death ◽  
Unexplained Death ◽  
Whole Exome

Introduction: Annually, thousands of sudden deaths in individuals under the age of 35 years remain unexplained following a medico-legal autopsy and are termed autopsy negative sudden unexplained death in the young (SUDY). Cardiomyopathies, channelopathies, and metabolic disorders may underlie a significant number of SUDY cases. Previously, we demonstrated that 25% of autopsy-negative SUDY cases had mutations in the 4 major cardiac ion channel genes ( KCNQ1, KCNH2, SCN5A , and RYR2 ). However, over 100 sudden death-susceptibility genes have been discovered and may be implicated in SUDY. Objective: We explored the utility of whole exome sequencing (WES) followed by gene-specific surveillance as an efficient and effective means of performing post-mortem genetic testing in SUDY. Methods: Postmortem WES was performed on 14 consecutively-referred white SUDY victims (57% men; average age at death 17.4 ± 8.6 years) using the Agilent SureSelect Human All Exon V4+UTR capture kit and an Illumina HiSeq 2000 sequencer. Following variant alignment (hg19) and annotation, 117 cardiac channelopathy-, cardiomyopathy-, and metabolic disorder-susceptibility genes were surveyed to identify putative SUDY-associated mutations. Potentially pathogenic variants had to be non-synonymous and ultra-rare [i.e. absent in all 3 evaluated exome databases (1,000 Genome Project, the NHLBI GO Exome Sequencing Project, and Exome Chip Design)]. Results: On average, each SUDY case had 12,758 ± 2016 non-synonymous variants, of which 79 ± 15 localized to the 117 evaluated genes. Overall, 8 unique, ultra-rare variants (7 missense, 1 in-frame insertion) identified in 6 genes (3 in TTN ; 1 each in CACNA1C, JPH2, MYH7, VCL, RYR2 ) were detected in 7 of 14 cases (50%). Of the 7 missense alterations, 2 (T171M- CACNA1C , I22160T- TTN ) were predicted damaging by 3 in-silico tools. Conclusions: Although WES and gene-specific surveillance is an efficient and effective strategy to detect rare, potentially lethal, genetic variants, the accurate interpretation of each variant is daunting. Importantly, rarity, even ultra-rarity, does not equal pathogenicity even when the ultra-rare variant resides within a so-called sudden death-susceptibility gene.

Whole exome and target sequencing identifies MAP2K5 as novel susceptibility gene for familial non-medullary thyroid carcinoma

2018 ◽  
Vol 144 (6) ◽  
pp. 1321-1330 ◽  
Author(s):  
Feng Ye ◽  
Hongwei Gao ◽  
Lin Xiao ◽  
Zhixiang Zuo ◽  
Yueping Liu ◽  
...  
Keyword(s):  
Thyroid Carcinoma ◽  
Medullary Thyroid Carcinoma ◽  
Susceptibility Gene ◽  
Medullary Thyroid ◽  
Target Sequencing ◽  
Whole Exome

Detection of Molecular Alterations in Taiwanese Patients with Medullary Thyroid Cancer Using Whole-Exome Sequencing

2018 ◽  
Vol 29 (4) ◽  
pp. 324-331 ◽  
Author(s):  
Ya-Sian Chang ◽  
Chun-Chi Chang ◽  
Hsi-Yuan Huang ◽  
Chien-Yu Lin ◽  
Kun-Tu Yeh ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Medullary Thyroid Cancer ◽  
Medullary Thyroid ◽  
Molecular Alterations ◽  
Whole Exome

Sipple's Syndrome: Description of One Case

1981 ◽  
Vol 67 (3) ◽  
pp. 245-248
Author(s):  
Enrico Dessy ◽  
Giuseppe Zucca ◽  
Gavino Faa ◽  
Maria Dolores Sofia
Keyword(s):  
Adrenal Gland ◽  
Thyroid Carcinoma ◽  
Medullary Thyroid Carcinoma ◽  
Young Woman ◽  
Correct Diagnosis ◽  
Family Members ◽  
Left Adrenal Gland ◽  
Medullary Thyroid

The case reported involves a young woman with a medullary thyroid carcinoma. Only during autopsy was it possible to show a pheochromocytoma of the left adrenal gland; multiple foci of atypical proliferation were observed, only microscopically, also in the adrenal gland. The authors emphasize the difficulty of a correct diagnosis during life and outline the necessity of an accurate screening of family members of a patient with Sipple's syndrome.

1265The results of whole exome sequencing in patients with bradyarrhythmias

EP Europace ◽  
2020 ◽  
Vol 22 (Supplement_1) ◽  
Author(s):  
E Polyakova ◽  
N Shcherbakova
Keyword(s):  
Family History ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Heart Diseases ◽  
Stress Test ◽  
Family Members ◽  
Pacemaker Implantation ◽  
Structural Heart Disease ◽  
Clinical Prognosis ◽  
Whole Exome

Abstract Introduction. Sick sinus syndrome (SSS) and atrioventricular block (AVB) are life-threatening cardiac arrhythmias, that sometimes can manifest itself with syncope and needs a pacemaker implantation even in children. Sometimes, SSS and AVB are accompanied by structural heart diseases such as septal defects, cardiomyopathies, but often the heart is structurally normal. Some genes associated with bradyarrhythmias are well known. At the same time, the etiology of the SSS is unidentified and may be genetic caused in 50% of patients with SSS. There are no studies on the prevalence of with bradyarrhythmia-associated mutations in children. The purpose of our work is to identify and study the types of mutations associated with SSS and AVB in children. Methods. We included in the study 15 patients (27% boys) with severe SSS and AVB, from the database of the Russian Pediatric Arrhythmia Center. 11 were the probands and 4 - family members.  Personal and family history, physical examination, including ECG, stress test, Holter monitoring, ECHO and other tests, and whole exome sequencing were made. The average age was 14.1 ± 4.5 (from 2 to 17). Results.  In 30% (5 pts) there was the combination of with bradyarrhythmias and structural heart disease. 7 pts (47%) had syncope, 4 pacemakers were implanted. 10 children (67%) had the genetic variants of genes associated with SSS and AVB: SCN5A, TNNI3K, KCNA5, TRPM4, ANK2 and others. Family history of cardiac diseases was positive in 5 probands; 2 probands had family members with implanted pacemakers. In 3 pts were likely pathogenic variants and in 7 pts - variants of unknown significance found. Conclusion.  We found the genetic cause of bradyarrhythmias in 67% of children. Further research and larger patient samples are required to study the prevalence of genetic types of and show the correlation of the genotype with the clinical prognosis. In addition, our work will enable practitioners to identify children from families with family forms of SSS, AVB and sudden cardiac death. Further research can help us determine the criteria for selecting children for genetic testing.

scholarly journals Whole-Exome Sequencing for the Identification of Susceptibility Genes of Kashin–Beck Disease

PLoS ONE ◽  
2014 ◽  
Vol 9 (4) ◽  
pp. e92298 ◽  
Author(s):  
Zhenxing Yang ◽  
Yu Xu ◽  
Hongrong Luo ◽  
Xiaohong Ma ◽  
Qiang Wang ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Susceptibility Genes ◽  
Whole Exome ◽  
Beck Disease

Whole-exome Sequencing Reveals New Potential Susceptibility Genes for Japanese Familial Pancreatic Cancer

2020 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Erina Takai ◽  
Hiromi Nakamura ◽  
Suenori Chiku ◽  
Emi Kubo ◽  
Akihiro Ohmoto ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Susceptibility Genes ◽  
Familial Pancreatic Cancer ◽  
Whole Exome

scholarly journals Whole-exome sequencing identifies GPSM1 as a susceptibility gene for premature ovarian insufficiency

2020 ◽  
Author(s):  
Xuzi Cai ◽  
Huijiao Fu ◽  
Yan Wang ◽  
Qiwen Liu ◽  
Xuefeng Wang
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Caspase 3 ◽  
Susceptibility Gene ◽  
Primordial Follicle ◽  
Antral Follicle ◽  
Premature Ovarian Insufficiency ◽  
Protein Signaling ◽  
Ovarian Insufficiency ◽  
Whole Exome

Abstract Background Genetic causes of premature ovarian insufficiency (POI) account for approximately 20~25% of patients. So far, only a few genes have been identified. Results Here, we first identified the c.1840C>A on G-protein signaling modulator 1 (GPSM1) as a susceptibility locus for POI in 10 sporadic POI patients by whole-exome sequencing. The frequency of GPSM1 c.1840C>A was then verified as 3/20 in a POI sample of 20 patients (including the above 10 patients) by Sanger sequencing. RT-PCR and western blot analysis showed the expression of GPSM1 in rat ovaries was increased in the large antral follicle stage compared to the primordial follicle stage (P<0.01). The cell proliferation assay (CCK8) and flow cytometry suggested that the small-interfering RNA-induced silencing of Gpsm1 significantly increased apoptosis and decreased proliferation of rat ovarian granulosa cells (GCs) (P<0.01). Furthermore, suppression of Gpsm1 in GCs reduced levels of cAMP, PKAc, p-CREB as well as the ratio of Bcl-2/Bax, and increased the expression of Caspase-3 and Cleaved Caspase-3 (P<0.01). Conclusions In summary, this study identified a susceptibility variant GPSM1 c.1840C>A of POI for the first time. Gpsm1 was related to rat follicle development, and silencing increased apoptosis and decreased proliferation in rat GCs, possibly through inhibition of the cAMP-PKA-CREB pathway. These findings facilitate the development of the early molecular diagnosis of POI.

scholarly journals Clinical implications of identifying pathogenic variants in aortic dissection patients with whole exome sequencing

2018 ◽  
Author(s):  
Brooke N. Wolford ◽  
Whitney E. Hornsby
Keyword(s):  
Family History ◽  
Aortic Dissection ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Family Members ◽  
Aortic Disease ◽  
Thoracic Aortic Dissection ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
History Of

ABSTRACTBackgroundThoracic aortic dissection is an emergent life-threatening condition. Routine screening for genetic variants causing thoracic aortic dissection is not currently performed for patients or their family members.MethodsWe performed whole exome sequencing of 240 patients with thoracic aortic dissection (n=235) or rupture (n=5) and 258 controls matched for age, sex, and ancestry. Blinded to case-control status, we annotated variants in 11 genes for pathogenicity.ResultsTwenty-four pathogenic variants in 6 genes (COL3A1, FBN1, LOX, PRKG1, SMAD3, TGFBR2) were identified in 26 individuals, representing 10.8% of aortic cases and 0% of controls. Among dissection cases, we compared those with pathogenic variants to those without and found that pathogenic variant carriers had significantly earlier onset of dissection (41 vs. 57 years), higher rates of root aneurysm (54% vs. 30%), less hypertension (15% vs. 57%), lower rates of smoking (19% vs. 45%), and greater incidence of aortic disease in family members. Multivariable logistic regression showed significant risk factors associated with pathogenic variants are age <50 [odds ratio (OR) = 5.5; 95% CI: 1.6-19.7], no history of hypertension (OR=5.6; 95% CI: 1.4-22.3) and family history of aortic disease (mother: OR=5.7; 95% CI: 1.4-22.3, siblings: OR=5.1; 95% CI 1.1-23.9, children: OR=6.0; 95% CI: 1.4-26.7).ConclusionsClinical genetic testing of known hereditary thoracic aortic dissection genes should be considered in patients with aortic dissection, followed by cascade screening of family members, especially in patients with age-of-onset of aortic dissection <50 years old, family history of aortic disease, and no history of hypertension.

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