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.

scholarly journals Clinical Implications of Identifying Pathogenic Variants in Individuals With Thoracic Aortic Dissection

2019 ◽  
Vol 12 (6) ◽  
Author(s):  
Brooke N. Wolford ◽  
Whitney E. Hornsby ◽  
Dongchuan Guo ◽  
Wei Zhou ◽  
Maoxuan Lin ◽  
...  
Keyword(s):  
Family History ◽  
Aortic Dissection ◽  
Age Of Onset ◽  
Family Members ◽  
Aortic Disease ◽  
Pathogenic Variant ◽  
Carrier Status ◽  
Thoracic Aortic Dissection ◽  
Pathogenic Variants ◽  
History Of

Background: Thoracic aortic dissection is an emergent life-threatening condition. Routine screening for genetic variants causing thoracic aortic dissection is not currently performed for patients or family members. Methods: We 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. Results: Twenty-four pathogenic variants in 6 genes (COL3A1, FBN1, LOX, PRKG1, SMAD3, and 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 versus 57 years), higher rates of root aneurysm (54% versus 30%), less hypertension (15% versus 57%), lower rates of smoking (19% versus 45%), and greater incidence of aortic disease in family members. Multivariable logistic regression showed that pathogenic variant carrier status was significantly associated with 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). Conclusions: Clinical genetic testing of known hereditary thoracic aortic dissection genes should be considered in patients with a thoracic aortic dissection, followed by cascade screening of family members, especially in patients with age-of-onset <50 years, family history of thoracic aortic disease, and no history of hypertension.

scholarly journals Whole-Exome Sequencing Identifies Germline IDH2 and IDH3 mutations That Predispose to Myeloid Neoplasms

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1405-1405 ◽  
Author(s):  
Remco Molenaar ◽  
Srinivasa Reddy Sanikommu ◽  
Bhumika J. Patel ◽  
Bartlomiej Przychodzen ◽  
Cornelis J van Noorden ◽  
...  
Keyword(s):  
Family History ◽  
General Population ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Family Members ◽  
Myeloid Cells ◽  
Enzyme Cytochemistry ◽  
Myeloid Neoplasms ◽  
Whole Exome ◽  
History Of

Abstract Background: Somatic mutations in isocitrate dehydrogenases 1 and 2 (IDH1/2MT) occur in up to 20% of certain types of myeloid neoplasms, chiefly MDS, MDS/MPN overlap and AML. These mutations induce a metabolic rewiring of cancer cells that affects alpha-ketoglutarate (aKG)-dependent dioxygenases such as TET2 DNA demethylases and Jumanji histone demethylases, which leads to global DNA and chromatin hypermethylation and leukemogenesis. In addition to somatic IDH1/2MT, germline IDH1/2MT occur in the context of Ollier and Maffucci syndromes which predispose to cartilaginous tumors and D 2HG aciduria, which predisposes to brain tumors. We hypothesized that germline mutations in IDH1/2 or the functionally related IDH3 may predispose to myeloid neoplasms. Methods: From 409 patients with MDS, MPN or AML, tumor samples from the myeloid compartment and germline samples from CD3+ lymphocytes were subjected to whole-exome sequencing. Myeloid cells were adhered to microscopy slides and maximal IDH3, IDH1/2 and, glucose-6-phosphate dehydrogenase (G6PD) glutamate dehydrogenase (GDH) activity was determined using quantitative enzyme cytochemistry. Results: In 409 patients with myeloid diseases, we found 8 patients with germline variants in IDH2 or IDH3. Combined, these variants occur more frequently in these 409 patients with myeloid neoplasms than in the general population (OR = 4.05, P=.0024), suggesting that germline IDH2/3MT predispose for myeloid diseases (Table 1). Of note, germline IDH2/3MT were completely mutually exclusive with somatic TET2MT, suggesting overlapping functions. Notably, all but one of these variants were indicated by two independent software programs to be deleterious for the enzymatic activity. To validate this, we determined maximal IDH3 activity in myeloid cells derived from a 47-year old AML patient with a germline IDH3MT (c.G626A, p.G209E) (and family history of leukemia) and her sister with IDH3WT. Maximal IDH3 activity was downregulated in the IDH3MT sample, while maximal IDH1/2, G6PD and GDH activity were unchanged (Fig. 1). 1 patient had a family history of MDS and 3 patients had a family history of colon, prostrate, gastric, lung and head and neck carcinoma in multiple family members. One patient had 4 family members affected with different cancers. The high age of the affected patients suggest that although germline IDH2/3MT may predispose to myeloid neoplasms, the development of disease occurs slowly. Discussion: Whereas somatic IDH2MT are common in MDS and other myeloid neoplasms, somatic IDH3MT are not frequently observed, nor in myeloid neoplasms, nor in other types of cancer that are regularly affected by IDH1/2MT. We show that deleterious germline IDH2/3MT may predispose to myeloid neoplasms and we postulate that this may occur via decreases in IDH2/3 activity. IDH3G209E is deleterious for IDH3 enzymatic function and may decrease intracellular aKG levels. This will restrict the function of aKG-dependent dioxygenases such as TET2 and Jumonji and mimic somatic IDH1/2MT and somatic inactivating TET2MT. This suggests that IDH1/2/3 are key enzymes and aKG is a central metabolite in maintaining normal function in myeloid cells. Given the family histories of 5/8 of the affected patients, screenings for germline IDH2/3 variants may reveal novel recurring IDH2/3MT that relate to various types of cancer. Representative photomicrographs of primary IDH3G209E MDS and IDH3WT myeloid cells after staining IDH3 activity in the presence of various isocitrate concentrations, IDH2 activity (1 mM isocitrate) and GDH activity (5 mM glutamate) using quantitative enzyme cytochemistry. The conversion of colorless tetrazolium salt to the purple formazan directly reflects enzyme activity thus darker cells have a higher maximal activity of the investigated enzyme. Table 1. Clinical characteristics from 6 patients with germline IDH2/3MT for which clinical information was available. Patient ID Age Diagnosis Gender OS (months) Variant SNP nr Occurrence in general population 1 50 RCMD F 23 IDH2T495M rs118053940 0,004848 2 66 CMML-1 M 46 IDH3AR360C rs116374996 0,004161 3 49 RAEB-1 F 16 IDH3BR359W rs377682152 0,000154 4 70 RCMD M 67 IDH2T495M rs118053940 0,004848 5 76 MDS-U F 17 IDH3BR334W rs374613588 0,00008 6 75 sAML M 5 IDH2R261H rs118101777 0,00177 Figure 1. Germline IDH3G209E mutation decreases maximal IDH3 activity, but not maximal IDH2 or GDH activity. Figure 1. Germline IDH3G209E mutation decreases maximal IDH3 activity, but not maximal IDH2 or GDH activity. Disclosures No relevant conflicts of interest to declare.

Abstract 16468: Results of Research Genetic Testing in Pediatric Cardiomyopathy Patients Justify Broader Clinical Genetic Testing

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Stephanie M Ware ◽  
Steven E Lipshultz ◽  
Steven D Colan ◽  
Ling Shi ◽  
Charles E Canter ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Family History ◽  
Risk Stratification ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Clinical Genetic ◽  
Clinical Genetic Testing ◽  
Whole Exome ◽  
Pediatric Cardiomyopathy ◽  
History Of

Introduction: Pediatric cardiomyopathies are genetically heterogeneous diseases with high risk of death or cardiac transplant. Despite progress in identifying causes, the majority of cases remain idiopathic. Currrently, genetic testing is not performed in all children with cardiomyopathy. Gene identification leads to better individual risk stratification and has the potential to stimulate the development of therapies based on the underlying mutation. The aim of this study is to identify genetic mutations in pediatric cardiomyopathy patients using whole exome sequencing. Hypothesis: Sarcomeric mutations are under-diagnosed causes of all forms of cardiomyopathy in children. Methods: Probands with cardiomyopathy were recruited from 11 institutions. Results of clinical genetic testing prior to enrollment were collected. Whole exome sequencing was performed and mutations were identified in 35 genes currently available on clinical genetic testing panels. Results: The initial 154 probands subjected to exome included 78 patients with DCM, 43 with HCM, 14 with RCM, and 19 with LVNC, mixed, or unknown types. Familial disease was present in 38% and the remainder were idiopathic. Twenty-seven percent had positive clinical genetic testing prior to enrollment. Exome testing identified mutations in 38 subjects who had not had clinical testing, increasing the cohort positive testing rate to 55% (DCM, 34.6%; HCM, 74.4%; RCM, 71.4%). Forty-five percent of subjects with no family history of disease had an identifiable mutation. Conclusions: Pediatric cardiomyopathy patients have a high incidence of mutations that can be identified by clinically available genetic testing. Lack of a family history of cardiomyopathy was not predictive of normal genetic testing. These results support the broader use of genetic testing in pediatric patients with all functional phenotypes of cardiomyopathy to identify disease causation allowing better family risk stratification.

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 to Identify Potential Genetic Risk in Substance Use Disorders: A Pilot Feasibility Study

2021 ◽  
Vol 10 (13) ◽  
pp. 2810
Author(s):  
P. V. AshaRani ◽  
Syidda Amron ◽  
Noor Azizah Bte Zainuldin ◽  
Sumanty Tohari ◽  
Alvin Y. J. Ng ◽  
...  
Keyword(s):  
Substance Use ◽  
Family History ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Substance Use Disorders ◽  
Feasibility Study ◽  
Genetic Variants ◽  
Addictive Disorders ◽  
Whole Exome ◽  
History Of

Genetics intersects with environmental, cultural, and social factors in the development of addictive disorders. This study reports the feasibility of whole-exome sequencing of trios (subject and two family members) to discover potential genetic variants in the development of substance use disorders (SUD). Family trios were recruited from the National Addictions Management Service in Singapore during the 2016–2018 period. Recruited subjects had severe alcohol use disorder (AUD) or opioid use disorder (OUD), with nicotine dependence (ND) and a family history of addictive disorders. Demographic characteristics and severity of addiction were captured. Whole-exome sequencing (WES) and analysis were performed on salivary samples collected from the trios. WES revealed variants in several genes in each individual and disruptive protein mutations in most. Variants were identified in genes previously associated with SUDs, such as Pleckstrin homology domain-containing family M member 3 (PLEKHM3), coiled-coil serine-rich protein 1 (CCSER1), LIM and calponin homology domains-containing protein 1 (LIMCH1), dynein axonemal heavy chain 8 (DNAH8), and the taste receptor type 2 member 38 (TAS2R38) involved in the perception of bitterness. The feasibility study suggests that subjects with a severe addiction profile, polysubstance use, and family history of addiction may often harbor gene variants that may predispose them to SUDs. This study could serve as a model for future precision medicine-based personalized interventional strategies for behavioral addictions and SUDs and for the discovery of potentially pathogenic genetic variants.

scholarly journals Osteogenesis Imperfecta With Cerebral Atherosclerosis: A Family Report

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A209-A209
Author(s):  
Junyu He ◽  
Zhihong Liao
Keyword(s):  
Osteogenesis Imperfecta ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Clinical Manifestation ◽  
Family Members ◽  
Whole Exome ◽  
The Family ◽  
Col1a2 Gene ◽  
History Of ◽  
Severe Fracture

Abstract Background: Osteogenesis imperfecta (OI) is a rare hereditary connective tissue disease. It is mainly associated with pathogenic variants in COL1A1 or COL1A2. Patients with OI usually have repeated history of bone fractures. Besides, osteogenesis imperfecta is associated with some cardiovascular complications, such as aortic and mitral valve dysfunction, aneurysm and aortic dissection. But the relationship between these diseases has not been well studied. Case Presentation: A 55-year-old man was admitted to our hospital mainly due to “dizziness for 2 hours”. He had a 4-month history of hypertension and a history of smoking for more than 20 years. He had no history of drinking alcohol. He had hunchback and O-type legs. Besides, the patient and some of his relatives had a history of repeated brittle fractures,which was considered as “osteogenesis imperfecta”. The clinical manifestation of OI in this family varies to a certain extent, from simple tooth disintegration to severe fracture deformity. The most serious patient of his family was unable to walk. CT and MRI revealed multiple systemic arteriosclerosis, including vertebral artery, posterior inferior cerebellar artery, cervical artery, and bilateral cerebellar multiple lacunar cerebral infarction. The blood sample of the patient was tested by whole exome sequencing, and the saliva samples of the patient’s family members were tested by Sanger sequencing. A mutation c.3159 + 2T &gt; A was detected in COL1A2 gene associated with OI, also found in the other affected family members, which had not been reported before. It was a segregating mutation in the family. The clinical severity of the family members was heterogeneous. Discussion: This case is worth learning from the following aspects: 1. A pathogenic heterozygous mutation, c.3159 + 2T &gt; A was detected in COL1A2 gene in the patient with OI, which is not reported in previous cases of OI. 2. The clinical manifestation of OI in this family varies to a certain extent, from simple tooth disintegration to severe fracture deformity. The most serious patient of his family was unable to walk. It presented the clinical heterogeneity of OI. Further basic researh on the mutation site of related gene of OI are needed. 3. We found the possibility of developing cerebral atherosclerosis in patients with OI. Therefore, patients with OI should give up smooking, exercise properly and keep on a low fat diet. They should pay attention to control blood pressure and blood lipid so as to reduce the risk of atherosclerosis. Conclusion: A c.3159 + 2T&gt;A mutation in COL1A2 gene detected by whole exome sequencing was the causing reason of OI, the discovery enriched the gene mutation spectrum of OI. We also found that OI may have relationship with premature atherosclerosis, and the abnormal bones of the cervical spine may lead to vertebrobasilar ischemia.

scholarly journals 99-Case Study of Sporadic Aortic Dissection by Whole Exome Sequencing Indicated Novel Disease-Associated Genes and Variants in Chinese Population

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Zanxin Wang ◽  
Xianmian Zhuang ◽  
Bailang Chen ◽  
Junmin Wen ◽  
Fang Peng ◽  
...  
Keyword(s):  
Correlation Analysis ◽  
Aortic Dissection ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Chinese Population ◽  
Enrichment Analysis ◽  
Copy Number Variations ◽  
Nucleotide Polymorphisms ◽  
Pathogenic Variants ◽  
Whole Exome

Background. In this study, the whole exome sequencing in human aortic dissection, a highly lethal cardiovascular disease, was investigated to explore the aortic dissection-associated genes and variants in Chinese population. Methods. Whole exome sequencing was performed in 99 cases of aortic dissection. All single nucleotide polymorphisms (SNPs), insertions/deletions (InDels), and copy number variations (CNVs) were filtered to exclude the benign variants. Enrichment analysis and disease-gene correlation analysis were performed. Results. 3425873 SNPs, 685245 InDels, and 1177 CNVs were identified, and aortic dissection-associated SNPs, InDels, and CNVs were collected. After the disease correlation analysis, 20 candidate genes were identified. Part of these genes such as MYH11, FBN1, and ACTA2 were consistent with previous studies, while MLX, DAB2IP, EP300, ZFYVE9, PML, and PRKCD were newly identified as candidate aortic dissection-associated genes. Conclusion. The pathogenic and likely pathogenic variants in most of AD-associated genes (FBN1, MYH11, EFEMP2, TGFBR2, FBN2, COL3A1, and MYLK) were identified in our cohort study, and pathogenic CNVs involved in MYH11, COL family, and FBN were also identified which are not detectable by other NGS analysis. The correlation between MLX, DAB2IP, EP300, ZFYVE9, PML, PRKCD, and aortic dissection was identified, and EP300 may play a key role in AD.

Abstract 17212: Whole Exome Sequencing Identifies Novel Genetic Variants in Left Ventricular Noncompaction Cardiomyopathy

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
John Collyer ◽  
Fuyi Xu ◽  
Undral Munkhsaikhan ◽  
Wenying Zhang ◽  
Lu Lu ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Left Ventricular ◽  
Left Ventricular Noncompaction ◽  
Ventricular Noncompaction ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
History Of ◽  
Left Ventricular Noncompaction Cardiomyopathy ◽  
Genotype Correlation

Introduction: Causal and modifier genes associated with left ventricular noncompaction (LVNC) often occurring in conjunction with other familial cardiomyopathies remain elusive. Hypothesis: The LVNC-associated di- and multigenic abnormalities can be identified by whole exome sequencing (WES). Methods: Five families with a history of LVNC, including five affected probands, three affected family members, and twelve unaffected relatives, were studied. Genomic DNA was extracted from whole blood samples followed by WES and Sanger sequencing to confirm possibly pathogenic variants predicted by in-silico analysis. Phenotype-genotype correlation and quantitative co-segregation studies are performed. Results: We identified nine missense possibly pathogenic variants, a 2-bp frameshift insertion, and a 9-bp in-frame insertion in the five families. Two affected siblings in Family 1 were found carrying digenic heterozygous variants: c.4048G>A (p.E1350K) in MYH7 and c.827C>T (p.A276V) in ANKRD1. Unaffected parents were carriers for each of the two variants. Three affected members, father and two daughters, of Family 2 carried c.550A>C (p.K184Q) variant in MYH7 in contrast to two unaffected members, mother and another daughter. In Family 3, multigenic heterozygosity (c.673G>T (p.D225Y) in CACNA2D1 ; c.440T>A (p.V147E) in COQ4 and c.3700C>A (p.H1234N) in MYH7) was identified in the proband. These variants were found in none of three unaffected relatives. The proband of Family 4 was positive for heterozygous variants: c.2684_2685insAG (p.A897Kfs*3) in DSC2 , c.8633T>C (p.V2878A) in OBSCN , and c.11717C >T (p.T3906I) in PLEC. The T3906I PLEC variant was identified in his unaffected half-sibling and his father, but not in his mother. In Family 5, c. 2591A>T (p.D864V) in HDAC9 , c.9616C>T (p.R3206W) in PLEC and c.954_955insT (p.L319Sfs*74) in MYH14 were identified in the proband. None of those variants were identified in his unaffected sibling. Conclusions: We report several potential pathogenic LVNC-associated variants in novel genes (ANKRD1, DSC2, OBSCN , PLEC, HDAC9, MYH14, COQ4, CACNA2D1) and known genes ( MYH7 and MYH7B). The diverse profile of inheritance (digenic and multigenic heterogeneity) that may cause and modify the heterogeneous LVNC phenotypes.

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