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ALU transposition induces familial hypertrophic cardiomyopathy
BACKGROUND: Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy (LVH) in the absence of predisposing cardiovascular conditions. Pathogenic variants in at least 16 cardiac sarcomeric genes have been implicated in HCM, most of which act in a dominant‐negative fashion. Ho...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978237/ https://www.ncbi.nlm.nih.gov/pubmed/31568709 http://dx.doi.org/10.1002/mgg3.951 |
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author | Nfonsam, Landry Huang, Lijia Carson, Nancy McGowan‐Jordan, Jean Beaulieu Bergeron, Melanie Goobie, Sharan Conacher, Susan McCarty, David Benson, Lee Hewson, Stacy Zahavich, Laura Sinclair‐Bourque, Elizabeth Smith, Amanda Potter, Ryan Ghani, Mahdi Bronicki, Lucas Jarinova, Olga |
author_facet | Nfonsam, Landry Huang, Lijia Carson, Nancy McGowan‐Jordan, Jean Beaulieu Bergeron, Melanie Goobie, Sharan Conacher, Susan McCarty, David Benson, Lee Hewson, Stacy Zahavich, Laura Sinclair‐Bourque, Elizabeth Smith, Amanda Potter, Ryan Ghani, Mahdi Bronicki, Lucas Jarinova, Olga |
author_sort | Nfonsam, Landry |
collection | PubMed |
description | BACKGROUND: Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy (LVH) in the absence of predisposing cardiovascular conditions. Pathogenic variants in at least 16 cardiac sarcomeric genes have been implicated in HCM, most of which act in a dominant‐negative fashion. However loss‐of‐function (haploinsufficiency) is the most common disease mechanism for pathogenic variants in MYBPC3, suggesting that MYBPC3 complete deletion may play a role in HCM pathogenesis. Here, we investigate MYBPC3 complete deletion as a disease mechanism in HCM by analyzing two unrelated patients with confirmed diagnosis of HCM that tested negative by Sanger sequencing analysis. METHODS: MYBPC3 complete deletion was investigated by Multiplex ligation‐dependent probe amplification (MLPA) and microarray analyses. The mechanism of deletion was investigated by interrogating the SINEBase database. RESULTS: Patient‐1 was diagnosed with nonobstructive HCM in his mid‐40s while undergoing assessment for palpitations, and patient‐2 with obstructive HCM in his late‐20s while undergoing systolic heart murmur assessment for an unrelated illness. MLPA testing revealed a heterozygous deletion of all MYBPC3 exons in both patients. Subsequent microarray testing confirmed these deletions which extended beyond the 5′ and 3′ ends of MYBPC3. Genomic assessment suggested that these deletions resulted from Alu/Alu‐homologous recombination. CONCLUSION: Our results demonstrate that haploinsufficiency resulting from MYBPC3 complete deletion, potentially mediated by Alu recombination, is an important disease mechanism in cardiomyopathy and emphasizes the importance of copy number variation analysis in patients clinically suspected of HCM. |
format | Online Article Text |
id | pubmed-6978237 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-69782372020-01-28 ALU transposition induces familial hypertrophic cardiomyopathy Nfonsam, Landry Huang, Lijia Carson, Nancy McGowan‐Jordan, Jean Beaulieu Bergeron, Melanie Goobie, Sharan Conacher, Susan McCarty, David Benson, Lee Hewson, Stacy Zahavich, Laura Sinclair‐Bourque, Elizabeth Smith, Amanda Potter, Ryan Ghani, Mahdi Bronicki, Lucas Jarinova, Olga Mol Genet Genomic Med Original Articles BACKGROUND: Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy (LVH) in the absence of predisposing cardiovascular conditions. Pathogenic variants in at least 16 cardiac sarcomeric genes have been implicated in HCM, most of which act in a dominant‐negative fashion. However loss‐of‐function (haploinsufficiency) is the most common disease mechanism for pathogenic variants in MYBPC3, suggesting that MYBPC3 complete deletion may play a role in HCM pathogenesis. Here, we investigate MYBPC3 complete deletion as a disease mechanism in HCM by analyzing two unrelated patients with confirmed diagnosis of HCM that tested negative by Sanger sequencing analysis. METHODS: MYBPC3 complete deletion was investigated by Multiplex ligation‐dependent probe amplification (MLPA) and microarray analyses. The mechanism of deletion was investigated by interrogating the SINEBase database. RESULTS: Patient‐1 was diagnosed with nonobstructive HCM in his mid‐40s while undergoing assessment for palpitations, and patient‐2 with obstructive HCM in his late‐20s while undergoing systolic heart murmur assessment for an unrelated illness. MLPA testing revealed a heterozygous deletion of all MYBPC3 exons in both patients. Subsequent microarray testing confirmed these deletions which extended beyond the 5′ and 3′ ends of MYBPC3. Genomic assessment suggested that these deletions resulted from Alu/Alu‐homologous recombination. CONCLUSION: Our results demonstrate that haploinsufficiency resulting from MYBPC3 complete deletion, potentially mediated by Alu recombination, is an important disease mechanism in cardiomyopathy and emphasizes the importance of copy number variation analysis in patients clinically suspected of HCM. John Wiley and Sons Inc. 2019-09-30 /pmc/articles/PMC6978237/ /pubmed/31568709 http://dx.doi.org/10.1002/mgg3.951 Text en © 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Articles Nfonsam, Landry Huang, Lijia Carson, Nancy McGowan‐Jordan, Jean Beaulieu Bergeron, Melanie Goobie, Sharan Conacher, Susan McCarty, David Benson, Lee Hewson, Stacy Zahavich, Laura Sinclair‐Bourque, Elizabeth Smith, Amanda Potter, Ryan Ghani, Mahdi Bronicki, Lucas Jarinova, Olga ALU transposition induces familial hypertrophic cardiomyopathy |
title |
ALU transposition induces familial hypertrophic cardiomyopathy |
title_full |
ALU transposition induces familial hypertrophic cardiomyopathy |
title_fullStr |
ALU transposition induces familial hypertrophic cardiomyopathy |
title_full_unstemmed |
ALU transposition induces familial hypertrophic cardiomyopathy |
title_short |
ALU transposition induces familial hypertrophic cardiomyopathy |
title_sort | alu transposition induces familial hypertrophic cardiomyopathy |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978237/ https://www.ncbi.nlm.nih.gov/pubmed/31568709 http://dx.doi.org/10.1002/mgg3.951 |
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