In a five-generation family carrying a novel frameshift LMNA variant (c.1434dupG, p.Leu479AlafsX72), imaging-augmented segregation analysis supports its association with lamin heart disease. Affected members exhibit conduction abnormalities, supraventricular and ventricular arrythmias, dilated cardiomyopathy with non-infarct pattern midwall septal fibrosis, heart failure and thromboembolic complications

Alfarih, M

Arbustini, E

Augusto, JB

Captur, G

Hughes, A

Lloyd, G

Lopes, LR

Mohiddin, S

Moon, JC

Syrris, P

English

UCL Discovery

159ORIGINAL ARTICLESFamilial cardiomyopathy caused by a novel heterozygous mutation in the gene LMNA (c.1434dupG): a cardiac MRI-augmented segregation studyMashael Alfarih1 2 3, Petros Syrris2, Eloisa Arbustini4, João B. Augusto1 2, Alun Hughes2 5,  Guy Lloyd1 2, Luis R. Lopes1 2, James C. Moon1 2, Saidi Mohiddin1 and Gabriella Captur1 2 5 61 Barts Heart Center, The Cardiovascular Magnetic Resonance Imaging Unit, St Bartholomew’s Hospital, West Smithfield, London, UK; 2 Institute of Cardiovascular Science, University College London, Gower Street, London, UK; 3 Department of Cardiac Technology, College of Applied Medial Sciences, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia; 4 Center for Inherited Cardiovascular Diseases, Foundation IRCCS Policlinico San Matteo, University of Pavia, Italy; 5 UCL MRC Unit for Lifelong Health and Ageing, 33 Bedford Place, London, UK; 6 Cardiology Department, Royal Free Hospital NHS Trust, Pond St, Hampstead, London, UKActa Myologica • 2019; XXXVIII: p. 159-162Address for correspondence: Gabriella Captur, Institute of Cardiovascular Science, University College London, Gower Street, London WC1E 6BT, UK. Tel. + 44 7809621264. E-mail: gabriella.captur@ucl.ac.uk   OPEN ACCESS © Gaetano Conte Academy - Mediterranean Society of MyologyIn a five-generation family carrying a novel frameshift LMNA variant (c.1434dupG, p.Leu479AlafsX72), imaging-augmented segregation analysis supports its association with lamin heart disease. Affected members exhibit conduction abnormalities, supraventricular and ventricular arrythmias, dilated car-diomyopathy with non-infarct pattern midwall septal fibrosis, heart failure and thromboembolic complications. Key words: familial dilated cardiomyopathy, lamin A/C, cardiola-minopathiesIntroduction Lamin A/C are structural intermediate filaments encoded by the LMNA gene. LMNA gene mutations are responsible for various multi-system laminopathies in-cluding lamin heart disease (LHD) which is characterized by cardiac conduction system disease (CCD), dilated car-diomyopathy (DCM), heart failure, malignant ventricular arrythmias (VA) and sudden cardiac death (1). Given the high arrhythmogenic risk, early recognition and interven-tion by implantable cardioverter defibrillator (ICD) can be life-saving.Defining pathogenicity of novel LMNA variants re-mains a challenge, but long-term surveillance of muta-tion-positive families permits segregation studies that are essential contributors to the validation of pathogenic mu-tations. Advanced tissue characterisation by cardiovascu-lar magnetic resonance (CMR) may help clinicians better understand the potential pathogenicity of variants, espe-cially when segregation studies include family members with borderline/subclinical phenotypes by other imaging modalities. Here we describe the deep clinical phenotypes as-sociated with a previously unreported LMNA variant: c.1434dupG. Case presentationWe report a family in which all affected members with cardiomyopathy (Fig. 1, left panel) carry the het-erozygous LMNA variant, c.1434dupG (Tab. 1). The vari-ant is predicted to disrupt protein reading frame creating a premature termination codon confirmed by Alamut® software. As variant pathogenicity was unknown we per-formed an imaging-assisted segregation study, demon-strating a link between variant and LHD. Within this five-generation family, four members are confirmed carriers of the variant by DNA testing, expressing a clinical phenotype that includes DCM, myocardial septal fibrosis [anecdotally found in 88% of LMNA gene mutation carriers (2)], supraventricular and ventricular arrhythmias, CCD, heart failure and throm-Mashael Alfarih et al.160boembolic complications (Tab. 2). There was a history of sudden death in seven members, interestingly all males [male gender is an adverse prognostic marker in LHD (3)]: proband II-10 died suddenly in his 40s likely from paternal inheritance of the variant as his father (I-1) died abruptly in his 50s (no genetic data available for Table 1. Novel LMNA genetic variant summary.Variant c.1434dupG, p.Leu479AlafsX72Mutation status Autosomal dominant, heterozygous Variant type Frameshift (truncation predicting mutation)Molecular consequence NM_170707: c.1434dupG: loss-of-function variantGenomic location Chr 1: 156,114,707-156,140,089Variant location Exon 8: Single nucleotide duplication, premature termination codon; downstream of the nuclear localization signal (NLS, exon 7) but upstream of the C-terminal tail** Recent data suggests that there is an association between more ad-verse cardiac phenotype and LMNA mutations upstream of the NLS or up-stream of the tail (Captur et al., 2018. Doi: 10.1136/openhrt-2018-000915).Phenotypic group Dilated cardiomyopathy-conduction disease (DCM-CD)GnomAD database Absent ClinVar clinical significance Not reportedACMG assertion of pathogenicity Pathogenic (Ia)Using American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria: the variant fulfills PVS1, PP1, PM2 and PP4 (1 x very strong, 1x moderate and 2 x supporting) implying pathogenicity.Type of analysis Direct fluorescent DNA sequencing for exon 8Figure 1. CMR-assisted segregation study for a family with novel LMNA frameshift variant c.1434dupG, p.Leu479AlafsX72 [Classification by ClinVar “not provided”; ACMG: “pathogenic (Ia)”; gnomAD: “absent”].Familial cardiomyopathy caused by a novel heterozygous mutation in the gene LMNA161the latter). Members I-1, II-1, II-5, II-6 and II-8 died young and unexpectedly (no genetic data available). Patient III-8 carries the variant and expresses an overt DCM phenotype together with atrial fibrillation (AF). Two of his children were also found to be carriers: IV-4 expressed DCM with heart failure, advanced CCD and ventricular arrhythmias that required an ICD. A DCM-pattern of extensive myocardial midwall septal fibrosis was noted by cardiovascular magnetic resonance (CMR) imaging. His brother IV-6, exhibited isolated right ven-tricular enlargement and biatrial dilatation in the con-text of AF, supraventricular arrhythmias and progressive CCD. Following multidisciplinary team (MDT) meeting discussion family member IV-6 received a primary pre-vention dual chamber ICD given his two risk factors for sudden cardiac death [male gender and non-missense LMNA mutation (4)]. His CMR similarly revealed mid-wall septal fibrosis matched by elevated native myocar-dial T1 times (Fig. 1, right panel). On follow-up, post-ICD, we detected a self-terminating ten-beat salvo of non-sustained ventricular tachycardia (VT).DNA testing in their sister IV-8 with normal CMR, excluded the presence of an LMNA mutation but iden-tified a variant of uncertain significance (VUS) in the Obscurin gene (OBSCN, c.21011C > G, p.Ser7004Cys). Although a few OBSCN mutations have been reported in the context of DCM and hypertrophic cardiomyopa-thy (5), their occurrence in heterozygous states in indi-viduals from the general population argue against their pathogenicity.DiscussionOur report describes a family in which the proband and affected family member harbour a novel potentially pathogenic mutation in LMNA gene (c.1434dupG). The mutation was not previously described in the literature, however the clinical course and ominous outcomes re-semble those reported in cardiolaminopathy. In this fam-ily there were seven premature sudden deaths  (6). In a multicentre study of 269 LMNA mutation carriers male gender, non-missense mutation, left ventricular ejection fraction < 45% and presence of non-sustained VT were found to be independent predictors of malignant VA (4). In this regard, member IV-4 with ICD satisfies all four risk factors whilst member IV-6 with progressive CCD and ICD scored positive for two risk factors (male, non-missense mutation). Pharmacological therapy in our LMNA gene mutation carriers with heart failure consisted of usual heart failure medications although in patients with bradyarrythmias, beta blockers were reserved till after device implantation or else discussed in a dedicated cardiomyopathy MDT meeting. Arrhythmias were managed according to stand-ard clinical practice, and all decisions related to device implantation were reached after considering SCD risk factors and broader MDT discussion.This pedigree analysis highlights the added value of CMR in segregation studies of LHD. For example, CMR potentially enables clinicians to better: 1) differ-entiate LMNA-DCM from other phenotypic mimics such Table 2. Family study-disease progression and results of electrocardiogram, 24-hour Holter and CMR.Family code Sex Genetic status Adverse events ECG/holter CMRmVA SCD CHF CVA DCM Brady SVT AVB A.Fib/FPAC/PVC LGEI-1 M NK(?) +II-1 M NK(?) +II-5 M NK(?) +II-6 M NK(?) +II-8 M NK(?) +II-10 M LMNA+ +III-3 F LMNA– – – – – – – – – – – –III-4 M LMNA– – – – – – – – – – – –III-7 F LMNA– – – – – – – – – – – –III-8 M LMNA+ + + + +IV-4 M LMNA+ + + + + + +IV-6 M LMNA+ + + + + +IV-8 F LMNA– – – – – – – – – – – –+/– Indicates presence/absence of the trait; blanks represent missing data. Abbreviations: A.Fib/F: atrial fibrillation/flutter; AVB: Atrio-ventricular block; Brady: bradyarrhythmia; CHF: congestive heart failure; CMR: cardiovascular magnetic resonance; DCM: dilated car-diomyopathy; ECG: electrocardiogram; F: female; LGE: late gadolinium enhancement; M: male; NK(?): Not known (genetic testing not done); PAC: Premature atrial contraction; PVC: premature ventricular contraction; SCD: sudden cardiac death; SVT: supraventricular tachycardia; mVA: malignant ventricular arrhythmia; LMNA+: LMNA gene mutation present; LMNA-: negative for LMNA gene mutation. Mashael Alfarih et al.162as arrhythmogenic cardiomyopathy; 2) exclude ischemic DCM using quantitative perfusion mapping approaches; 3) monitor LHD progression over time; 4) detect sub-clinical phenotypes otherwise missed by other imaging modalities; 5) plan optimal timing of device implantation in patients with borderline phenotypes as part of a multi-disciplinary team meeting discussion. Previous CMR work reported that non-ischaemic (midwall) scar in patients with LHD and VA predomi-nantly involved the basal septum, basal inferior wall, and sub-aortic mitral continuity  (7), which tallies with our current data. Member IV-6 had non-infarct pattern mid-wall LGE in the basal-to-mid septum matched by high myocardial T1 but normal T2 times, suggesting true myo-cardial septal fibrosis. Indeed he had QRS fragmentation on ECG (Fig. 1, right panel). Limitations include that other genomic changes in this family cannot be definitively excluded, CMR was not performed on all family members, and genetic data una-vailable for the five family members in generations I/II with premature sudden deaths. Conclusions LMNA frameshift variant (c.1434dupG) seems to be causative of lamin heart disease on the basis of this CMR-augmented segregation analysis however further studies are necessary to confirm our hypothesis.Acknowledgment The authors are grateful to Dr. Rachel Kearns (Uni-versity college London Hospital), Ms. Ellie Quinn (Barts Heart Center) and Ms. Chrysoula Dalageorgou (Univer-sity College London), for their valuable assistance and comments that greatly improved the manuscript.FundingThis study was funded by National Institute for Health Research Rare Diseases Translational Research Collaboration (NIHR RD-TRC, #171603).Conflicts of interestThe Authors declare to have no conflict of interest.References1. Peretto G, Sala S, Benedetti S, et al. Updated clinical overview on cardiac laminopathies: an electrical and mechanical disease. Nucleus 2018;9:380-91. https://doi.org/10.1080/19491034.2018.1489195.2. Holmström M, Kivistö S, Heliö T, et al. Late gadolinium enhanced cardiovascular magnetic resonance of lamin A/C gene muta-tion related dilated cardiomyopathy.  J Cardiovasc Magn Reson 2011;13:30. https://doi.org/10.1186/1532-429X-13-30.3. Pasotti M, Klersy C, Pilotto A, et al. Long-term outcome and risk stratification in dilated cardiolaminopathies. J Am Coll Cardiol 2008;52:1250-60. https://doi.org/10.1016/j.jacc.2008.06.0444. Priori S, Lundqvist C, Mazzant A, et al. ESC Guidelines for the management of patients with ventricular arrhythmias and the pre-vention of sudden cardiac death. Eur Heart J 2015;36:2793-867. https://doi.org/:10.1093/eurheartj/ehv3165. Marston S, Montgiraud C, Munster AB, et al. OBSCN mutations associated with dilated cardiomyopathy and haploinsufficiency. PloS One 2015;10:e0138568.6. Bécane H, Bonne G, Varnous S, et al. High incidence of sudden death with conduction system and myocardial disease due to lamins A and C gene mutation Pacing Clin Electrophysiol 2000;23:1661-6. https://doi.org/10.1046/j.1460-9592.2000.01661.x7. Kumar S, Androulakis AF, Sellal JM, et al. Multicenter experience with catheter ablation for ventricular tachycardia in lamin A/C car-diomyopathy. Circ Arrhythm Electrophysiol 2016;9: pii: e004357. https://doi.org/10.1161/CIRCEP.116.004357.How to cite this article: Alfarih M, Syrris P, Arbustini E, et al. Familial cardiomyopathy caused by a novel heterozygous mutation in the gene LMNA (c.1434dupG): a cardiac MRI-augmented segregation study. Acta Myol 2019;38:159-62.This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

Familial cardiomyopathy caused by a novel heterozygous mutation in the gene LMNA (c.1434dupG): a cardiac MRI-augmented segregation study

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Familial cardiomyopathy caused by a novel heterozygous mutation in the gene LMNA (c.1434dupG): a cardiac MRI-augmented segregation study

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