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 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 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.

scholarly journals Whole-exome sequencing reveals a novel homozygous mutation in the COQ8B gene associated with nephrotic syndrome

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mohd Fareed ◽  
Vikas Makkar ◽  
Ravi Angral ◽  
Mohammad Afzal ◽  
Gurdarshan Singh
Keyword(s):  
Nephrotic Syndrome ◽  
Disease Management ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Homozygous Mutation ◽  
Consanguineous Family ◽  
Clinical Prognosis ◽  
Whole Exome ◽  
Recurrent Mutations ◽  
Ckd Stage

AbstractNephrotic syndrome arising from monogenic mutations differs substantially from acquired ones in their clinical prognosis, progression, and disease management. Several pathogenic mutations in the COQ8B gene are known to cause nephrotic syndrome. Here, we used the whole-exome sequencing (WES) technology to decipher the genetic cause of nephrotic syndrome (CKD stage-V) in a large affected consanguineous family. Our study exposed a novel missense homozygous mutation NC_000019.9:g.41209497C > T; NM_024876.4:c.748G > A; NP_079152.3:p.(Asp250Asn) in the 9th exon of the COQ8B gene, co-segregated well with the disease phenotype. Our study provides the first insight into this homozygous condition, which has not been previously reported in 1000Genome, ClinVar, ExAC, and genomAD databases. In addition to the pathogenic COQ8B variant, the WES data also revealed some novel and recurrent mutations in the GLA, NUP107, COQ2, COQ6, COQ7 and COQ9 genes. The novel variants observed in this study have been submitted to the ClinVar database and are publicly available online with the accessions: SCV001451361.1, SCV001451725.1 and SCV001451724.1. Based on the patient's clinical history and genomic data with in silico validation, we conclude that pathogenic mutation in the COQ8B gene was causing kidney failure in an autosomal recessive manner. We recommend WES technology for genetic testing in such a consanguineous family to not only prevent the future generation, but early detection can help in disease management and therapeutic interventions.

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.

scholarly journals Case Report: An Infant With Kabuki Syndrome, Alobar Holoprosencephaly and Truncus Arteriosus: A Case for Whole Exome Sequencing in Neonates With Congenital Anomalies

2021 ◽  
Vol 12 ◽  
Author(s):  
Rishika P. Sakaria ◽  
Parul G. Zaveri ◽  
Shannon Holtrop ◽  
Jie Zhang ◽  
Chester W. Brown ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Congenital Anomalies ◽  
Large Scale ◽  
Heart Diseases ◽  
Truncus Arteriosus ◽  
Kabuki Syndrome ◽  
Whole Exome ◽  
Anomalous Pulmonary Venous Return ◽  
Spectrum Of Patients

Kabuki syndrome is a rare multiple anomalies syndrome associated with mutations in KMT2D or KDM6A. It is characterized by infantile hypotonia, developmental delay and/or intellectual disability, long palpebral fissures with everted lateral third of the lower eyelids and typical facial features. Intracranial anomalies occur infrequently in patients with KS and holoprosencephaly has only been recently described. Additionally, though congenital heart diseases are common in patients with KS, to our knowledge truncus arteriosus has never been reported in a patient with KS. We present an unusual case of KS in an infant with holoprosencephaly and truncus arteriosus with partial anomalous pulmonary venous return. Duo whole exome sequencing in our patient identified a pathogenic nonsense variant in exon 10 of KMT2D (c.2782C &gt; T; p. Gln928*) establishing the diagnosis. This report further expands the phenotypic spectrum of patients with Kabuki syndrome and emphasizes the utility of performing large scale sequencing in neonates with multiple congenital anomalies.

276 A new face for an old foe?

2018 ◽  
Vol 89 (10) ◽  
pp. A40.3-A40 ◽  
Author(s):  
Sangha Gavinda ◽  
Bron Anthony ◽  
Donaghy Michael ◽  
Evans Cerys ◽  
Hardcastle Alison ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Family Members ◽  
Calcium Sensitivity ◽  
Actin Binding ◽  
Cranial Neuropathy ◽  
Limb Weakness ◽  
Proteolytic Cascade ◽  
Whole Exome ◽  
Novel Variant

BackgroundMutations in the protein gelsolin result in hereditary systemic amyloidosis, characterised by onset of corneal lattice dystrophy in the third decade, a slowly progressive cranial neuropathy and cutis laxa. To date four dominantly inherited gelsolin mutations have been identified, two mutations resulting in the classical syndrome and two mutations resulting in renal-predominant amyloidosis.MethodsWe identified a family in which four individuals in three generations presented with corneal lattice dystrophy and neurological symptoms. Detailed clinical neurological and ophthalmological assessment and investigations including neurophysiology and imaging were performed. Whole exome sequencing was undertaken in three family members.ResultsWhole exome sequencing revealed a novel variant in the gelsolin gene (c. G1738A; p. E580K), dominantly inherited and predicted to be pathogenic. Examination, neurophysiological testing and imaging revealed the presence of distal upper limb weakness and wasting, corneal lattice dystrophy and cervical myelopathy in all affected family members.ConclusionThe E580K mutation described in this family is in a conserved calcium-sensitive actin-binding domain that displays sequence homology with other actin-depolymerising proteins. Mutations in this domain may result in abnormal gelsolin-actin interactions and changes in calcium sensitivity may render the protein susceptible to the same aberrant proteolytic cascade as with other known mutations.

scholarly journals A Novel CRYBB2 Stopgain Mutation Causing Congenital Autosomal Dominant Cataract in a Chinese Family

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Yu Zhou ◽  
Yaru Zhai ◽  
Lulin Huang ◽  
Bo Gong ◽  
Jie Li ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Congenital Cataract ◽  
Autosomal Dominant ◽  
Family Members ◽  
Chinese Family ◽  
Heterozygous Mutation ◽  
Whole Exome ◽  
Causal Mutation ◽  
Control Samples

Congenital cataract is the most common cause of the visual disability and blindness in childhood. This study aimed to identify gene mutations responsible for autosomal dominant congenital cataract (ADCC) in a Chinese family using next-generation sequencing technology. This family included eight unaffected and five affected individuals. After complete ophthalmic examinations, the blood samples of the proband and two available family members were collected. Then the whole exome sequencing was performed on the proband and Sanger sequencing was applied to validate the causal mutation in the two family members and control samples. After the whole exome sequencing data were filtered through a series of existing variation databases, a heterozygous mutation c.499T<G (p.E167X) in CRYBB2 gene was found. And the results showed that the mutation cosegregated with the disease phenotype in the family and was absolutely absent in 1000 ethnicity-matched control samples. Thus, the heterozygous mutation c.499T<G (p.E167X) in CRYBB2 was the causal mutation responsible for this ADCC family. In conclusion, our findings revealed a novel stopgain mutation c.499T<G (p.E167X) in the exon 6 of CRYBB2 which expanded the mutation spectrum of CRYBB2 in Chinese congenital cataract population and illustrated the important role of CRYBB2 in the genetics research of congenital cataract.

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.

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