Application of Whole Exome Sequencing in the Clinical Diagnosis and Management of Inherited Cardiovascular Diseases in Adults

Seidelmann, Sara B.; Smith, Emily; Subrahmanyan, Lakshman; Dykas, Daniel; Ziki, Maen D. Abou; Azari, Bani; Hannah‐Shmouni, Fady; Jiang, Youxing; Akar, Joseph G.; Marieb, Mark M.; Jacoby, Daniel; Bale, Allen E.; Lifton, Richard P.; Mani, Arya

doi:10.1161/circgenetics.116.001573

Cited by 54 publications

(38 citation statements)

References 40 publications

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“…Siedelmann et al. reported that diagnosis was reached in 26.5% of patients (53 of 200 patients) who had familial cardiovascular disease at statistically higher rate than in our study ( p = .024 by Fisher's Exact test) (Seidelmann et al., ). Consistent with this, in their cohort of patients from families with multiple affected family members with CHD, Jia et al.…”

Section: Discussioncontrasting

confidence: 58%

Experience with genomic sequencing in pediatric patients with congenital cardiac defects in a large community hospital

Hauser

Solomon²,

Vilboux³

et al. 2018

Molec Gen & Gen Med

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BackgroundCongenital cardiac defects, whether isolated or as part of a larger syndrome, are the most common type of human birth defect occurring on average in about 1% of live births depending on the malformation. As there is an expanding understanding of the underlying molecular mechanisms by which a cardiac defect may occur, there is a need to assess the current rates of diagnosis of cardiac defects by molecular sequencing in a clinical setting.Methods and ResultsIn this report, we evaluated 34 neonatal and pediatric patients born with a cardiac defect and their parents using exomized preexisting whole genome sequencing (WGS) data to model clinically available exon‐based tests. Overall, we identified candidate variants in previously reported cardiac‐related genes in 35% (12/34) of the probands. These include clearly pathogenic variants in two of 34 patients (6%) and variants of uncertain significance in relevant genes in 10 patients (26%), of these latter 10, 2 segregated with clinically apparent findings in the family trios.ConclusionsThese findings suggest that with current knowledge of the proteins underlying CHD, genomic sequencing can identify the underlying genetic etiology in certain patients; however, this technology currently does not have a high enough yield to be of routine clinical use in the screening of pediatric congenital cardiac defects.

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Section: Discussioncontrasting

confidence: 58%

Experience with genomic sequencing in pediatric patients with congenital cardiac defects in a large community hospital

Hauser

Solomon²,

Vilboux³

et al. 2018

Molec Gen & Gen Med

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“…Seidelmann et al 41 reported their experience with WES in a variety of inherited cardiovascular conditions, including HCM. In 28 HCM patients, 13/28 (46.4%) had pathogenic or likely pathogenic variants identified; twelve occurred in genes found on current cardiomyopathy panels.…”

Section: Discussionmentioning

confidence: 99%

A Comparison of Whole Genome Sequencing to Multigene Panel Testing in Hypertrophic Cardiomyopathy Patients

Cirino

Lakdawala

McDonough

et al. 2017

Circ Cardiovasc Genet

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Background As DNA sequencing costs decline, genetic testing options have expanded. Whole exome and whole genome sequencing (WGS) are entering clinical use, posing questions about their incremental value compared with disease-specific multi-gene panels that have been the cornerstone of genetic testing. Methods and Results Forty-one patients with hypertrophic cardiomyopathy (HCM) who had undergone targeted HCM genetic testing (either multi-gene panel or familial variant test) were recruited into the MedSeq Project, a clinical trial of WGS. Results from panel genetic testing and WGS were compared. In 20 of 41 participants panel genetic testing identified variants classified as pathogenic, likely pathogenic or uncertain significance (VUS). WGS identified 19 of these 20 variants but the variant detection algorithm missed a pathogenic 18-base pair duplication in MYBPC3 due to low coverage. In 3 individuals, WGS identified variants in genes implicated in cardiomyopathy but not included in panel testing: a pathogenic PTPN11 variant and VUSs in ILK and FLNC. WGS also identified 84 secondary findings (mean=2/person, range= 0–6), which mostly defined carrier status for recessive conditions. Conclusions WGS detected nearly all variants identified on panel testing, provided one new diagnostic finding, and allowed interrogation of posited disease genes. Several variants of uncertain clinical utility and numerous secondary genetic findings were also identified. While panel testing and WGS provided similar diagnostic yield, WGS offered the advantage of re-analysis over time to incorporate advances in knowledge, but necessitated expertise in genomic interpretation to appropriately incorporate WGS into clinical care.

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“…Notably, the vast majority of these studies have been performed in pediatric populations and in cancer patients. Hence, the value of WES in the diagnosis and management of adult patients with nononcological diseases is only recently emerging . In fact, in adult hepatology clinic, Wilson's disease, hemochromatosis, and alpha‐1 antitrypsin deficiency are routinely investigated as part of a comprehensive work‐up for liver test abnormalities and/or advanced liver disease by using single gene and/or gene panel test(s).…”

Section: Where Could Hepatologists Be Missing Liver‐related Genetic Tmentioning

confidence: 99%

Exome Sequencing in Clinical Hepatology

Vilarinho¹,

Mistry

2019

Hepatology

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The clinical relevance of the Human Genome Project and next‐generation sequencing technology was demonstrated for the first time in 2009, when whole‐exome sequencing (WES) provided the definitive diagnosis of congenital chloride diarrhea in an infant with presumed renal salt‐wasting disease. Over the past decade, numerous studies have shown the utility of WES for clinical diagnosis as well as for discovery of novel genetic disorders through analysis of a single or a handful of informative pedigrees. Hence, advances in improving the speed, accuracy, and computational analysis combined with exponential decrease in the cost of sequencing the human genome is transforming the practice of medicine. The impact of WES has been most noticeable in pediatric disorders and oncology, but its utility in the liver clinic is recently emerging. Here, we assess the current status of WES for clinical diagnosis and acceleration of translation research to enhance care of patients with liver disease.

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Application of Whole Exome Sequencing in the Clinical Diagnosis and Management of Inherited Cardiovascular Diseases in Adults

Cited by 54 publications

References 40 publications

Experience with genomic sequencing in pediatric patients with congenital cardiac defects in a large community hospital

Experience with genomic sequencing in pediatric patients with congenital cardiac defects in a large community hospital

A Comparison of Whole Genome Sequencing to Multigene Panel Testing in Hypertrophic Cardiomyopathy Patients

Exome Sequencing in Clinical Hepatology

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