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Hereditary hypertrophic cardiomyopathy in children and young adults—The value of reevaluating and expanding gene panel analyses

Fernlund, Eva LU orcid ; Kissopoulou, Antheia ; Green, Henrik ; Karlsson, Jan Erik LU ; Ellegård, Rada ; Årstrand, Hanna Klang ; Jonasson, Jon and Gunnarsson, Cecilia (2020) In Genes 11(12).
Abstract

Introduction: Sudden cardiac death (SCD) and early onset cardiomyopathy (CM) in the young will always lead to suspicion of an underlying genetic disorder. Incited by the rapid advances in genetic testing for disease we have revisited families, which previously tested “gene-negative” for familial predominantly pediatric CM, in hopes of finding a causative gene variant. Methods: 10 different families with non-syndromic pediatric CM or hypertrophic cardiomyopathy (HCM) with severe disease progression and/or heredity for HCM/CM related SCD with “gene-negative” results were included. The index patient underwent genetic testing with a recently updated gene panel for CM and SCD. In case of failure to detect a pathogenic variant in a relevant... (More)

Introduction: Sudden cardiac death (SCD) and early onset cardiomyopathy (CM) in the young will always lead to suspicion of an underlying genetic disorder. Incited by the rapid advances in genetic testing for disease we have revisited families, which previously tested “gene-negative” for familial predominantly pediatric CM, in hopes of finding a causative gene variant. Methods: 10 different families with non-syndromic pediatric CM or hypertrophic cardiomyopathy (HCM) with severe disease progression and/or heredity for HCM/CM related SCD with “gene-negative” results were included. The index patient underwent genetic testing with a recently updated gene panel for CM and SCD. In case of failure to detect a pathogenic variant in a relevant gene, the index patient and both parents underwent clinical (i.e., partial) exome sequencing (trio-exome) in order to catch pathogenic variants linked to the disease in genes that were not included in the CM panel. Results: The mean age at clinical presentation of the 10 index cases was 12.5 years (boys 13.4 years, n = 8; girls 9 years, n = 2) and the family history burden was 33 HCM/CM cases including 9 HCM-related SCD and one heart transplantation. In 5 (50%) families we identified a genetic variant classified as pathogenic or likely pathogenic, in accordance with the American College of Medical Genetics and Genomics (ACMG) criteria, in MYH7 (n = 2), RBM20, ALPK3, and PGM1, respectively, and genetic variants of unknown significance (VUS) segregating with the disease in an additional 3 (30%) families, in MYBPC3, ABCC9, and FLNC, respectively. Conclusion: Our results show the importance of renewed thorough clinical assessment and the necessity to challenge previous genetic test results with more comprehensive updated gene panels or exome sequencing if the initial test failed to identify a causative gene for early onset CM or SCD in children. In pediatric cardiomyopathy cases when the gene panel still fails to detect a causative variant, a trio exome sequencing strategy might resolve some unexplained cases, especially if a multisystemic condition is clinically missed.

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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Exome sequencing, Gene panel, Hypertrophic, Pediatric cardiomyopathy, Sudden cardiac death
in
Genes
volume
11
issue
12
article number
1472
pages
18 pages
publisher
MDPI AG
external identifiers
  • pmid:33302605
  • scopus:85097432737
ISSN
2073-4425
DOI
10.3390/genes11121472
language
English
LU publication?
yes
id
913a72f8-dab5-4a41-a5db-356e594d9837
date added to LUP
2020-12-22 09:38:05
date last changed
2024-11-15 20:38:21
@article{913a72f8-dab5-4a41-a5db-356e594d9837,
  abstract     = {{<p>Introduction: Sudden cardiac death (SCD) and early onset cardiomyopathy (CM) in the young will always lead to suspicion of an underlying genetic disorder. Incited by the rapid advances in genetic testing for disease we have revisited families, which previously tested “gene-negative” for familial predominantly pediatric CM, in hopes of finding a causative gene variant. Methods: 10 different families with non-syndromic pediatric CM or hypertrophic cardiomyopathy (HCM) with severe disease progression and/or heredity for HCM/CM related SCD with “gene-negative” results were included. The index patient underwent genetic testing with a recently updated gene panel for CM and SCD. In case of failure to detect a pathogenic variant in a relevant gene, the index patient and both parents underwent clinical (i.e., partial) exome sequencing (trio-exome) in order to catch pathogenic variants linked to the disease in genes that were not included in the CM panel. Results: The mean age at clinical presentation of the 10 index cases was 12.5 years (boys 13.4 years, n = 8; girls 9 years, n = 2) and the family history burden was 33 HCM/CM cases including 9 HCM-related SCD and one heart transplantation. In 5 (50%) families we identified a genetic variant classified as pathogenic or likely pathogenic, in accordance with the American College of Medical Genetics and Genomics (ACMG) criteria, in MYH7 (n = 2), RBM20, ALPK3, and PGM1, respectively, and genetic variants of unknown significance (VUS) segregating with the disease in an additional 3 (30%) families, in MYBPC3, ABCC9, and FLNC, respectively. Conclusion: Our results show the importance of renewed thorough clinical assessment and the necessity to challenge previous genetic test results with more comprehensive updated gene panels or exome sequencing if the initial test failed to identify a causative gene for early onset CM or SCD in children. In pediatric cardiomyopathy cases when the gene panel still fails to detect a causative variant, a trio exome sequencing strategy might resolve some unexplained cases, especially if a multisystemic condition is clinically missed.</p>}},
  author       = {{Fernlund, Eva and Kissopoulou, Antheia and Green, Henrik and Karlsson, Jan Erik and Ellegård, Rada and Årstrand, Hanna Klang and Jonasson, Jon and Gunnarsson, Cecilia}},
  issn         = {{2073-4425}},
  keywords     = {{Exome sequencing; Gene panel; Hypertrophic; Pediatric cardiomyopathy; Sudden cardiac death}},
  language     = {{eng}},
  number       = {{12}},
  publisher    = {{MDPI AG}},
  series       = {{Genes}},
  title        = {{Hereditary hypertrophic cardiomyopathy in children and young adults—The value of reevaluating and expanding gene panel analyses}},
  url          = {{http://dx.doi.org/10.3390/genes11121472}},
  doi          = {{10.3390/genes11121472}},
  volume       = {{11}},
  year         = {{2020}},
}