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Lamin mutation location predicts cardiac phenotype severity: combined analysis of the published literature

Captur, G; James, M; Petros, S; William, M; Eloisa, A; DIna, R; Ben, O; (2018) Lamin mutation location predicts cardiac phenotype severity: combined analysis of the published literature. Open Heart , 5 (2) , Article e000915. 10.1136/openhrt-2018-000915. Green open access

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Abstract

OBJECTIVE: Two LMNA genotype–phenotype cardiac correlations are reported: first, that cardiac involvement in multisystem laminopathies prevails with mutations upstream of the nuclear localisation signal (NLS); second, that worse outcomes occur with non-missense (compared with missense) mutations. We tested whether LMNA mutation DNA location and mutation subtype can predict phenotype severity in patients with lamin heart disease. METHODS: We used a semantic workflow platform and manual electronic literature search to identify published LMNA mutations with cardiac-predominant phenotype. Hierarchical cluster analysis (HCA) assembled lamin heart disease into classes based on phenotype severity. 176 reported causative mutations were classified and any relationships to mutation location/subtype assessed by contingency analysis. RESULTS: More adverse phenotype was associated with mutation location upstream of the NLS (p=0.014, OR 2.38, 95% CI 1.19 to 4.80) but not with non-missense mutations (p=0.337, OR 1.36, 95% CI 0.72 to 2.57), although an association with non-missense mutations was identified in a subcluster with malignant ventricular arrhythmia (p=0.005, OR 2.64, 95% CI 0.76 to 9.21). HCA limited to the 65 mutations described on ClinVar as pathogenic/likely pathogenic showed similar findings (upstream of NLS, p=0.030, OR 4.78, 95% CI 1.28 to 17.83; non-missense, p=0.121, OR 2.64, 95% CI 0.76 to 9.21) as did analysis limited to pathogenic/likely pathogenic variants according to the American College of Medical Genetics and Genomics standards. CONCLUSION: Cardiac patients with an LMNA mutation located upstream versus downstream of the NLS have a more adverse cardiac phenotype, and some missense mutations can be as harmful as non-missense ones.

Type: Article
Title: Lamin mutation location predicts cardiac phenotype severity: combined analysis of the published literature
Open access status: An open access version is available from UCL Discovery
DOI: 10.1136/openhrt-2018-000915
Publisher version: https://doi.org/10.1136/openhrt-2018-000915
Language: English
Additional information: This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Institute of Cardiovascular Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Institute of Cardiovascular Science > Clinical Science
URI: http://discovery.ucl.ac.uk/id/eprint/10061300
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