Applying High-Resolution Variant Classification to Cardiac Arrhythmogenic Gene Testing in a Demographically Diverse Cohort of Sudden Unexplained Deaths

Ying, Lin; Williams, Nori; Wang, Dawei; Coetzee, William A.; Zhou, Bo; Eng, Lucy S.; Um, Sung Yon; Bao, Rong; Devinsky, Orrin; McDonald, Thomas V.; Sampson, Barbara A.; Tang, Yingying

doi:10.1161/circgenetics.117.001839

Cited by 30 publications

(32 citation statements)

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“…This percentage is higher than even the demographic breakdown of the City of New York, with Black or African Americans making up 24.3% of the population ("United States Census Bureau", ). However, previous studies have shown that there is not an enrichment of P/LP variants in this population compared to others (Lin et al, ). The overrepresentation of the Black/African American population in our cohort may be due to an intrinsic factor not identified here, or the well‐documented barriers to care in minority populations (Espejo et al, ; Hayes, Riley, Radley, & McCarthy, ; Rositch, Atnafou, Krakow, & D'Souza, ).…”

Section: Discussioncontrasting

confidence: 64%

“…The overrepresentation of the Black/African American population in our cohort may be due to an intrinsic factor not identified here, or the well‐documented barriers to care in minority populations (Espejo et al, ; Hayes, Riley, Radley, & McCarthy, ; Rositch, Atnafou, Krakow, & D'Souza, ). While this is not a novel discovery, as previous cohort study has elucidated such disparities (Lin et al, ), it is important to reiterate the point that people from underrepresented populations should be included in research.…”

Section: Discussionmentioning

confidence: 84%

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Lessons learned from testing cardiac channelopathy and cardiomyopathy genes in individuals who died suddenly: A two‐year prospective study in a large medical examiner’s office with an in‐house molecular genetics laboratory and genetic counseling services

Williams

Manderski

Stewart

et al. 2019

Journal of Genetic Counseling

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This is a comprehensive review and analysis of 254 cases tested consecutively in the in‐house College of American Pathologist‐accredited molecular genetics laboratory within the New York City Office of Chief Medical Examiner between October 2015 and February 2018, using a multigene cardiac panel composed of 95 genes associated with cardiac channelopathy and cardiomyopathy. Demographics, autopsy findings, medical history, and postmortem genetic testing results were collected for each case. The majority of decedents were adults (>25 years old, 52.7%), followed by infants (<12 months, 25.6%), young adults (19–25 years old, 11.4%), and children (1–18 years old, 10.2%). There were more males (64.2%) than females (35.8%). The racial/ethnic composition of decedents was 40.2% Black, 29.9% Hispanic, 22.4% White, 5.1% Asian/Pacific Islander, and 2.8% mixed/unspecified. Overall, 45.7% of decedents had a negative autopsy, and the remaining had one to four cardiac findings (cardiac hypertrophy, dilation, atherosclerosis, and fatty change). Twenty‐seven pathogenic/likely pathogenic variants (P/LP) and 99 variants of uncertain significance (VUS) were identified in 10.6% and 39% of decedents respectively. P/LP and VUS were found in 51 cardiac genes of the total 95 genes, where MYBPC3, TTN (predicted truncating variants), KCNH2, RYR2 and DSP genes had more than two P/LP variants identified. Among the 73 decedents who were suspected of having cardiac arrhythmia or cardiomyopathy, 20.3% had P/LP variants and 47.9% had VUS; among 23 decedents who had hypertensive cardiovascular diseases and 20 decedents with a history of substance use, 13% and 30% had P/LP variants, respectively. There were 26 referrals from medical examiners for genetic counseling and the outcomes are discussed. The study demonstrates characteristics of the diverse population typically seen by medical examiners in an urban center and our results support a broader implementation of molecular testing in sudden death.

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Section: Discussioncontrasting

confidence: 64%

Section: Discussionmentioning

confidence: 84%

Lessons learned from testing cardiac channelopathy and cardiomyopathy genes in individuals who died suddenly: A two‐year prospective study in a large medical examiner’s office with an in‐house molecular genetics laboratory and genetic counseling services

Williams

Manderski

Stewart

et al. 2019

Journal of Genetic Counseling

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“…The purpose of these studies was to functionally examine HCN4 VUS identified in our previous work, where we performed variant classification using genetic screening of a cardiac arrhythmogenic testing panel of ∼300 cases of sudden unexplained deaths . In the latter study, we have identified four HCN4 VUS and one likely benign (LB) variant.…”

Section: Resultsmentioning

confidence: 99%

“…With the power of massively parallel sequencing, testing a large number of cardiac disease‐associated genes simultaneously has become feasible. There are now several reports of postmortem testing to identify pathogenic variants directly linked to an underlying heritable cardiac disease; hence, the potential for fatal arrhythmia and sudden death . When there is insufficient evidence to classify variants as either benign or pathogenic, they are considered variants of uncertain significance (VUS).…”

Section: Introductionmentioning

confidence: 99%

“…When there is insufficient evidence to classify variants as either benign or pathogenic, they are considered variants of uncertain significance (VUS). In our previous study in which 89 cardiac genes were analyzed in a large cohort of 296 sudden unexpected deaths (SUD), we identified a large preponderance of VUS in various genes, including the pacemaker gene, HCN4 .…”

Section: Introductionmentioning

confidence: 99%

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Functional reclassification of variants of uncertain significance in the HCN4 gene identified in sudden unexpected death

Dong

Subbotina

Williams

et al. 2019

Pacing Clinical Electrophis

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The HCN4 gene encodes a subunit of the hyperpolarization‐activated cyclic nucleotide‐gated channel, type 4 that is essential for the proper generation of pacemaker potentials in the sinoatrial node. The HCN4 gene is often present in targeted genetic testing panels for various cardiac conduction system disorders and there are several reports of HCN4 variants associated with conduction disorders. Here, we report the in vitro functional characterization of four rare variants of uncertain significance (VUS) in HCN4, identified through testing a cohort of 296 sudden unexpected natural deaths. The variants are all missense alterations, leading to single amino acid changes: p.E66Q in the N‐terminus, p.D546N in the C‐linker domain, and both p.S935Y and p.R1044Q in the C‐terminus distal to the CNBD. We also identified a likely benign variant, p. P1063T, which has a high minor allele frequency in the gnomAD, which is utilized here as a negative control. Three of the HCN4 VUS (p.E66Q, p.S935Y, and p.R1044Q) had electrophysiological characteristics similar to the wild‐type channel, suggesting that these variants are benign. In contrast, the p.D546N variant in the C‐linker domain exhibited a larger current density, slower activation, and was unresponsive to cyclic adenosine monophosphate (cAMP) compared to wild‐type. With functional assays, we reclassified three rare HCN4 VUS to likely benign variants, eliminating the necessity for costly and time‐consuming further study. Our studies also provide a new lead to investigate how a VUS located in the C‐linker connecting the pore to the cAMP binding domain may affect the channel open state probability and cAMP response.

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Genetic Variants Associated With Unexplained Sudden Cardiac Death in Adult White and African American Individuals

et al. 2021

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IMPORTANCEUnexplained sudden cardiac death (SCD) describes SCD with no cause identified. Genetic testing helps to diagnose inherited cardiac diseases in unexplained SCD; however, the associations between pathogenic or likely pathogenic (P/LP) variants of inherited cardiomyopathies (CMs) and arrhythmia syndromes and the risk of unexplained SCD in both White and African American adults living the United States has never been systematically examined.OBJECTIVE To investigate cases of unexplained SCD to determine the frequency of P/LP genetic variants of inherited CMs and arrhythmia syndromes. DESIGN, SETTING, AND PARTICIPANTSThis genetic association study included 683 African American and White adults who died of unexplained SCD and were included in an autopsy registry. Overall, 413 individuals had DNA of acceptable quality for genetic sequencing. Data were collected from January 1995 to December 2015. A total of 30 CM genes and 38 arrhythmia genes were sequenced, and variants in these genes, curated as P/LP, were examined to study their frequency. Data analysis was performed from June 2018 to March 2021. MAIN OUTCOMES AND MEASURESThe frequency of P/LP variants for CM or arrhythmia in individuals with unexplained SCD. RESULTSThe median (interquartile range) age at death of the 413 included individuals was 41 (29-48) years, 259 (62.7%) were men, and 208 (50.4%) were African American adults. A total of 76 patients (18.4%) with unexplained SCD carried variants considered P/LP for CM and arrhythmia genes. In total, 52 patients (12.6%) had 49 P/LP variants for CM, 22 (5.3%) carried 23 P/LP variants for arrhythmia, and 2 (0.5%) had P/LP variants for both CM and arrhythmia. Overall, 41 P/LP variants for hypertrophic CM were found in 45 patients (10.9%), 9 P/LP variants for dilated CM were found in 11 patients (2.7%), and 10 P/LP variants for long QT syndrome were found in 11 patients (2.7%). No significant difference was found in clinical and heart characteristics between individuals with or without P/LP variants. African American and White patients were equally likely to harbor P/LP variants. CONCLUSIONS AND RELEVANCEIn this large genetic association study of community cases of unexplained SCD, nearly 20% of patients carried P/LP variants, suggesting that genetics may contribute to a significant number of cases of unexplained SCD. Our findings regarding both the association of unexplained SCD with CM genes and race-specific genetic variants suggest new avenues of study for this poorly understood entity.

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Applying High-Resolution Variant Classification to Cardiac Arrhythmogenic Gene Testing in a Demographically Diverse Cohort of Sudden Unexplained Deaths

Abstract: High-resolution variant interpretation provides diagnostic accuracy and healthcare efficiency. Under-represented populations warrant greater inclusion in future studies.

Cited by 30 publications

References 24 publications

Lessons learned from testing cardiac channelopathy and cardiomyopathy genes in individuals who died suddenly: A two‐year prospective study in a large medical examiner’s office with an in‐house molecular genetics laboratory and genetic counseling services

Lessons learned from testing cardiac channelopathy and cardiomyopathy genes in individuals who died suddenly: A two‐year prospective study in a large medical examiner’s office with an in‐house molecular genetics laboratory and genetic counseling services

Functional reclassification of variants of uncertain significance in the HCN4 gene identified in sudden unexpected death

Genetic Variants Associated With Unexplained Sudden Cardiac Death in Adult White and African American Individuals

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