Utility of genetics for risk stratification in pediatric hypertrophic cardiomyopathy

Children with hypertrophic cardiomyopathy (HCM) experience sudden cardiac death (SCD) and other life‐threatening events. We assessed if affected gene and variant burden predict outcomes. Patients

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Published in:Clinical genetics 2018-02, Vol.93 (2), p.310-319
Main Authors: Mathew, J., Zahavich, L., Lafreniere‐Roula, M., Wilson, J., George, K., Benson, L., Bowdin, S., Mital, S.
Format: Article
Language:English
Subjects:
Cardiomyopathy
Children
Defibrillators
Electrocardiography
genetics
Heart diseases
hypertrophic cardiomyopathy
Insertion
myectomy
myosin
Pediatrics
sudden death
Transplantation
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cited_by cdi_FETCH-LOGICAL-c4547-3254e5afffbb3681e0829e56800dae7d6d54aefdd82f683ef3e577b8fd75f8fd3
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container_end_page 319
container_issue 2
container_start_page 310
container_title Clinical genetics
container_volume 93
creator Mathew, J.
Zahavich, L.
Lafreniere‐Roula, M.
Wilson, J.
George, K.
Benson, L.
Bowdin, S.
Mital, S.
description Children with hypertrophic cardiomyopathy (HCM) experience sudden cardiac death (SCD) and other life‐threatening events. We assessed if affected gene and variant burden predict outcomes. Patients
doi_str_mv 10.1111/cge.13157
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We assessed if affected gene and variant burden predict outcomes. Patients &lt;18 years old with primary HCM with a pathogenic variant or variant of uncertain significance in cardiomyopathy genes were included. Association of gene and variant number and type with freedom from major adverse cardiac events (MACE), that is, ICD insertion, myectomy, aborted SCD, transplantation or death, was assessed by Cox regression. A total of 98 of 155 gene‐tested patients carried a non‐benign variant. The primary affected gene was MYH7 in 35% (MYH7+) and MYBPC3 in 49% (MYBPC3+). MYH7+ patients had earlier disease onset and higher risk of MACE (hazard ratio 2.7, 95% CI 1.3‐5.7). Risk of MACE was also higher in patients with multiple variants (n = 16) (HR 2.5, CI: 1.1‐5.9) compared to a propensity score‐matched single variant subset, after adjustment for primary gene, and in patients with de novo (n = 18) vs inherited variants (HR 5.7, CI: 2.6‐12.7). Affected gene (eg, MYH7), higher variant burden and de novo variant status are independently associated with earlier onset and higher frequency of adverse outcomes in pediatric HCM, highlighting the importance of genetic risk stratification in HCM. Affected gene, overall higher variant burden, and de novo variant status were associated with earlier onset and worse outcomes in children with HCM.</description><identifier>ISSN: 0009-9163</identifier><identifier>EISSN: 1399-0004</identifier><identifier>DOI: 10.1111/cge.13157</identifier><identifier>PMID: 29053178</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>Cardiomyopathy ; Children ; Defibrillators ; Electrocardiography ; genetics ; Heart diseases ; hypertrophic cardiomyopathy ; Insertion ; myectomy ; myosin ; Pediatrics ; sudden death ; Transplantation</subject><ispartof>Clinical genetics, 2018-02, Vol.93 (2), p.310-319</ispartof><rights>2017 The Authors. 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We assessed if affected gene and variant burden predict outcomes. Patients &lt;18 years old with primary HCM with a pathogenic variant or variant of uncertain significance in cardiomyopathy genes were included. Association of gene and variant number and type with freedom from major adverse cardiac events (MACE), that is, ICD insertion, myectomy, aborted SCD, transplantation or death, was assessed by Cox regression. A total of 98 of 155 gene‐tested patients carried a non‐benign variant. The primary affected gene was MYH7 in 35% (MYH7+) and MYBPC3 in 49% (MYBPC3+). MYH7+ patients had earlier disease onset and higher risk of MACE (hazard ratio 2.7, 95% CI 1.3‐5.7). Risk of MACE was also higher in patients with multiple variants (n = 16) (HR 2.5, CI: 1.1‐5.9) compared to a propensity score‐matched single variant subset, after adjustment for primary gene, and in patients with de novo (n = 18) vs inherited variants (HR 5.7, CI: 2.6‐12.7). Affected gene (eg, MYH7), higher variant burden and de novo variant status are independently associated with earlier onset and higher frequency of adverse outcomes in pediatric HCM, highlighting the importance of genetic risk stratification in HCM. Affected gene, overall higher variant burden, and de novo variant status were associated with earlier onset and worse outcomes in children with HCM.</description><subject>Cardiomyopathy</subject><subject>Children</subject><subject>Defibrillators</subject><subject>Electrocardiography</subject><subject>genetics</subject><subject>Heart diseases</subject><subject>hypertrophic cardiomyopathy</subject><subject>Insertion</subject><subject>myectomy</subject><subject>myosin</subject><subject>Pediatrics</subject><subject>sudden death</subject><subject>Transplantation</subject><issn>0009-9163</issn><issn>1399-0004</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><recordid>eNp1kMFKAzEQhoMotlYPvoAseNHDtkmz2WyOUmoVCl7a85JuJm3qdrMmKbJvb2qrB8E5zPDDx8fwI3RL8JDEGVVrGBJKGD9DfUKFSDHG2TnqxyNSQXLaQ1feb2OknIlL1BsLzCjhRR8tlsHUJnSJ1ckaGgim8om2LnHGvyc-OBmMNlXctklMk7SgjAzOVMmma8EFZ9tNDJV0ythdZ1sZNt01utCy9nBzugO0fJ4uJi_p_G32Onmap1XGMp7SMcuASa31akXzggAuxgJYXmCsJHCVK5ZJ0EoVY50XFDQFxvmq0IozHTcdoIejt3X2Yw8-lDvjK6hr2YDd-5IIlmEerVlE7_-gW7t3TfwuUgLznBbsQD0eqcpZ7x3osnVmJ11XElweqi5j1eV31ZG9Oxn3qx2oX_Kn2wiMjsCnqaH731ROZtOj8gt7o4kr</recordid><startdate>201802</startdate><enddate>201802</enddate><creator>Mathew, J.</creator><creator>Zahavich, L.</creator><creator>Lafreniere‐Roula, M.</creator><creator>Wilson, J.</creator><creator>George, K.</creator><creator>Benson, L.</creator><creator>Bowdin, S.</creator><creator>Mital, S.</creator><general>Blackwell Publishing Ltd</general><scope>24P</scope><scope>WIN</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-7643-4484</orcidid></search><sort><creationdate>201802</creationdate><title>Utility of genetics for risk stratification in pediatric hypertrophic cardiomyopathy</title><author>Mathew, J. ; Zahavich, L. ; Lafreniere‐Roula, M. ; Wilson, J. ; George, K. ; Benson, L. ; Bowdin, S. ; Mital, S.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4547-3254e5afffbb3681e0829e56800dae7d6d54aefdd82f683ef3e577b8fd75f8fd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Cardiomyopathy</topic><topic>Children</topic><topic>Defibrillators</topic><topic>Electrocardiography</topic><topic>genetics</topic><topic>Heart diseases</topic><topic>hypertrophic cardiomyopathy</topic><topic>Insertion</topic><topic>myectomy</topic><topic>myosin</topic><topic>Pediatrics</topic><topic>sudden death</topic><topic>Transplantation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mathew, J.</creatorcontrib><creatorcontrib>Zahavich, L.</creatorcontrib><creatorcontrib>Lafreniere‐Roula, M.</creatorcontrib><creatorcontrib>Wilson, J.</creatorcontrib><creatorcontrib>George, K.</creatorcontrib><creatorcontrib>Benson, L.</creatorcontrib><creatorcontrib>Bowdin, S.</creatorcontrib><creatorcontrib>Mital, S.</creatorcontrib><collection>Wiley-Blackwell Open Access Collection</collection><collection>Wiley Online Library</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Clinical genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mathew, J.</au><au>Zahavich, L.</au><au>Lafreniere‐Roula, M.</au><au>Wilson, J.</au><au>George, K.</au><au>Benson, L.</au><au>Bowdin, S.</au><au>Mital, S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Utility of genetics for risk stratification in pediatric hypertrophic cardiomyopathy</atitle><jtitle>Clinical genetics</jtitle><addtitle>Clin Genet</addtitle><date>2018-02</date><risdate>2018</risdate><volume>93</volume><issue>2</issue><spage>310</spage><epage>319</epage><pages>310-319</pages><issn>0009-9163</issn><eissn>1399-0004</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>Children with hypertrophic cardiomyopathy (HCM) experience sudden cardiac death (SCD) and other life‐threatening events. We assessed if affected gene and variant burden predict outcomes. Patients &lt;18 years old with primary HCM with a pathogenic variant or variant of uncertain significance in cardiomyopathy genes were included. Association of gene and variant number and type with freedom from major adverse cardiac events (MACE), that is, ICD insertion, myectomy, aborted SCD, transplantation or death, was assessed by Cox regression. A total of 98 of 155 gene‐tested patients carried a non‐benign variant. The primary affected gene was MYH7 in 35% (MYH7+) and MYBPC3 in 49% (MYBPC3+). MYH7+ patients had earlier disease onset and higher risk of MACE (hazard ratio 2.7, 95% CI 1.3‐5.7). Risk of MACE was also higher in patients with multiple variants (n = 16) (HR 2.5, CI: 1.1‐5.9) compared to a propensity score‐matched single variant subset, after adjustment for primary gene, and in patients with de novo (n = 18) vs inherited variants (HR 5.7, CI: 2.6‐12.7). 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source Wiley Online Library
subjects Cardiomyopathy
Children
Defibrillators
Electrocardiography
genetics
Heart diseases
hypertrophic cardiomyopathy
Insertion
myectomy
myosin
Pediatrics
sudden death
Transplantation
title Utility of genetics for risk stratification in pediatric hypertrophic cardiomyopathy
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