Gene-Based Risk Stratification for Cardiac Disorders in
            <i>LMNA</i>
            Mutation Carriers

Nishiuchi, Suguru; Makiyama, Takeru; Aiba, Takeshi; Nakajima, Kenzaburo; Hirose, Sachiko; Kohjitani, Hirohiko; Yamamoto, Yuta; Harita, Takeshi; Hayano, Mamoru; Wuriyanghai, Yimin; Chen, Jia‐Rong; Sasaki, Kenji; Yagihara, Nobue; Ishikawa, Taisuke; Onoue, Kenji; Murakoshi, Nobuyuki; Watanabe, Ichiro; Ohkubo, Kimie; Watanabe, Hiroshi; Ohno, Seiko; Doi, Takahiro; Shizuta, Satoshi; Minamino, Tohru; Saito, Yoshihiko; Oginosawa, Yasushi; Nogami, Akihiko; Aonuma, Kazutaka; Kusano, Kengo; Makita, Naomasa; Shimizu, Wataru; Horie, Minoru; Kimura, Takeshi

doi:10.1161/circgenetics.116.001603

Cited by 67 publications

(53 citation statements)

References 37 publications

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“…Whether TTN truncating variants could predict clinical outcomes in the longer-term remain to be established in larger studies 15 . By contrast, accumulating evidence proved that DCM associated with LMNA variants had a higher risk for sudden cardiac death (SCD), cardiac transplantation, cardiac conduction disturbance, and atrial or ventricular arrhythmias [20][21][22] , indicating their potential role in risk stratification 23 . With limited power, our analysis did not show a genotype-phenotype correlation between LMNA variants and risk for the primary outcome.…”

Section: Discussionmentioning

confidence: 99%

Genetic Basis and Genotype–Phenotype Correlations in Han Chinese Patients with Idiopathic Dilated Cardiomyopathy

Zhang

Xie

Lan

et al. 2020

Sci Rep

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Dilated cardiomyopathy (DcM) is one of the leading causes of heart failure. A large proportion of genetic cause remains unexplained, especially in idiopathic DcM. We performed target next-generation sequencing of 102 genes which were known causes or candidate genes for cardiomyopathies and channelpathies in 118 prospectively recruited Han Chinese patients with idiopathic DCM. 41 of the 118 patients carried 40 pathogenic or likely pathogenic variants, providing a molecular diagnosis in 34.7% of patients. 32 of these variants were novel. TTN truncating variants were predominant, with a frequency of 31.0%, followed by variants of LMNA (14.3%), RBM20 (4.8%), and NEXN (4.8%). These 4 genes accounted for over half variants identified. No significant difference in clinical characteristics or rates of reaching the composite end point (cardiac transplantation and death from cardiac causes) between pathogenic or likely pathogenic variant carriers and noncarriers (hazard ratio 1.11, 95% CI: 0.41 to 3.00), or between patients with TTN truncating variants or without (hazard ratio 0.49, 95% CI: 0.36 to 6.10). In our prospective study, we first determined the overall genetic profiles and genotype-phenotype correlations in Han Chinese idiopathic DCM patients, which could provide insight for genetic diagnosis of DcM in this population.Dilated cardiomyopathy (DCM) is the one of the leading causes of heart failure and sudden death, and the most common cause of heart transplantation, affecting approximately 1 in 250 individuals 1 . DCM is a progressive disease, with 50% of patients reported to die within 5 years of diagnosis without transplantation 2 . DCM frequently has a genetic etiology, and multiple causative genes have been discovered. The genetic basis of DCM is highly diverse; over 30 genes have been identified as the potentially disease-causing genes 1,3 . About 25-30% of individuals with DCM have a familial form of the disease 1,4 . Truncating variants in TTN, which encodes titin, account for up to 25% of familial DCM 5 . A large proportion of genetic cause of DCM remains unexplained, especially in idiopathic DCM 6 .Next-generation sequencing (NGS) approaches have enabled rapid genetic testing, particularly for large genes such as TTN which are hard to sequence with traditional methods. Using NGS, researchers have characterized the genetic atlas of DCM in Caucasian population 7,8 . Zhao and colleagues performed NGS of 25 genes in 21 Chinese patients 9 , but the number of genes and patients were limited, and the most commonly pathogenic gene in DCM-TTN was not included in their sequencing panel. Also, understanding the potential genotype-phenotype correlations may identify high-risk patients in this condition. In this study, we developed a custom "cardiomyopathy panel" containing 102 genes which were known causes or candidate genes for cardiomyopathies and channelpathies. We prospectively recruited 118 unrelated patients with idiopathic DCM and performed target NGS in this cohort to determine the molecular characterization o...

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Section: Discussionmentioning

confidence: 99%

Genetic Basis and Genotype–Phenotype Correlations in Han Chinese Patients with Idiopathic Dilated Cardiomyopathy

Zhang

Xie

Lan

et al. 2020

Sci Rep

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“…The type of mutation (truncation‐predicting/non‐missense mutation vs. missense mutation) is one of the factors that are confirmed in many clinical series to be associated with the potential severity of the cardiac phenotype. Non‐missense mutations (ins‐del/truncating, or mutations affecting splicing) are a risk factor for malignant ventricular arrhythmias and early onset of cardiac manifestations, including children . This effect is also confirmed by clinical studies in large families .…”

Section: Factors Contributing To the Interpretation Of The Pathologicmentioning

confidence: 99%

“…However, most mutations in LMNA are missense. Many of them are validated in large clinical series and are associated with recurrently similar phenotypes (p.Glu161Lys, p.Arg190Trp, p.Glu317Lys) (http://www.umd.be/LMNA) characterized by CCD, arrhythmias, left ventricular dysfunction and progressive evolution to end‐stage heart failure requiring transplantation . Recurrent mutations, however, are a minority of all missense mutations in LMNA gene .…”

Section: Factors Contributing To the Interpretation Of The Pathologicmentioning

confidence: 99%

Lamin missense mutations—the spectrum of phenotype variability is increasing

Captur

Bilińska

Arbustini

2018

European J of Heart Fail

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“…Наиболее характерными клиническими проявлениями ламинопатий являются нарушения проводимости, желудочковые и наджелудочковые нарушения ритма, а также систолическая дисфункция миокарда. Пенетрантность заболевания очень высока и составляет >90% в возрасте 45 лет [5]. Показано, что к 30 годам >90% носителей мутаций в гене LMNA имеют фенотипические проявления заболевания в виде нарушений ритма и проводимости, а к 60 годам пенетрантность по данным признакам достигает 100% [5].…”

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“…Пенетрантность заболевания очень высока и составляет >90% в возрасте 45 лет [5]. Показано, что к 30 годам >90% носителей мутаций в гене LMNA имеют фенотипические проявления заболевания в виде нарушений ритма и проводимости, а к 60 годам пенетрантность по данным признакам достигает 100% [5]. Систолическая дисфункция (фракция выброса (ФВ) левого желудочка (ЛЖ) <50%) регистрируется примерно у 20% пациентов при первом обращении, но доля таких пациентов прогрессивно нарастает и достигает 52% в течение последующих пяти лет [6].…”

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Clinical and diagnostic difficulties in management of patients with laminopathies

et al. 2019

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Российский кардиологический журнал 2019; 24 (10)Mutations in the LMNA gene cause developing of several phenotypes, both with isolated involvement of cardiac, muscle, adipose and bone tissues, and with their combination. The dominance of cardiovascular signs in the clinical performance and false clarity in nosology definition can cause underestimation of subclinical markers of other systems partaking. It leads to an incorrect interpretation of the true disease etiology, failure in genetic diagnostics, and untimely determination of the correct management and prognosis. The article presents clinical cases that demonstrate both the most typical manifestations of laminopathy and rare combinations of symptoms, which represent a certain diagnostic difficulty.

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Gene-Based Risk Stratification for Cardiac Disorders in LMNA Mutation Carriers

Abstract: The truncation mutations were associated with manifestation of cardiac phenotypes in -related cardiomyopathy, suggesting that genetic analysis might be useful for diagnosis and risk stratification.

Cited by 67 publications

References 37 publications

Genetic Basis and Genotype–Phenotype Correlations in Han Chinese Patients with Idiopathic Dilated Cardiomyopathy

Genetic Basis and Genotype–Phenotype Correlations in Han Chinese Patients with Idiopathic Dilated Cardiomyopathy

Lamin missense mutations—the spectrum of phenotype variability is increasing

Clinical and diagnostic difficulties in management of patients with laminopathies

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