A Complex Double Deletion in
 LMNA
 Underlies Progressive Cardiac Conduction Disease, Atrial Arrhythmias, and Sudden Death

Marsman, Roos F.; Bardai, Abdennasser; Postma, Alex V.; C.J., Jan; Koopmann, Tamara T.; Beekman, Leander; Wal, Allard C. van der; Pinto, Yigal M.; Deprez, Ronald H. Lekanne; Wilde, Arthur A.M.; Jordaens, Luc; Bezzina, Connie R.

doi:10.1161/circgenetics.110.959221

Cited by 24 publications

(7 citation statements)

References 45 publications

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“…[21][22][23][24] In LMNA mutation carriers, non-missense mutations may result in more severe cardiac events such as malignant ventricular arrhythmias than from missense mutations. 21,23) Van Rijsingen et al evaluated risk factors for malignant ventricular arrhythmias in a multicenter cohort of 269 LMNA mutation carriers and found that non-missense mutations (indels, truncating mutations, or mutations affecting splicing) were an independent risk factor for malignant ventricular arrhythmias.…”

Section: Discussionmentioning

confidence: 99%

A Novel Truncating LMNA Mutation in Patients with Cardiac Conduction Disorders and Dilated Cardiomyopathy

et al. 2018

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SummaryThe cardiac phenotype of laminopathies is characterized by cardiac conduction disorders (CCDs) and dilated cardiomyopathy (DCM). Although laminopathies have been considered monogenic, they exhibit a remarkable degree of clinical variability. This case series aimed to detect the causal mutation and to investigate the causes of clinical variability in a Japanese family with inherited CCD and DCM. Of the five family members investigated, four had either CCD/DCM or CCD alone, while one subject had no cardiovascular disease and acted as a normal control. We performed targeted resequencing of 174 inherited cardiovascular diseaseassociated genes in this family and pathological mutations were confirmed using Sanger sequencing. The degree of clinical severity and variability were also evaluated using long-term medical records. We discovered a novel heterozygous truncating lamin A/C (LMNA) mutation (c.774delG) in all four subjects with CCD. Because this mutation was predicted to cause a frameshift mutation and premature termination (p.Gln258HisfsTer222) in LMNA, we believe that this LMNA mutation was the causal mutation in this family with CCD and laminopathies. In addition, gender-specific intra-familiar clinical variability was observed in this Japanese family where affected males exhibited an earlier onset of CCD and more severe DCM compared to affected females. Using targeted resequencing, we discovered a novel truncating LMNA mutation associated with CCD and DCM in this family characterized by gender differences in clinical severity in LMNA carriers. Our results suggest that in patients with laminopathy, clinical severity may be the result of multiple factors.(Int Heart J 2018; 59: 531-541)

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Section: Discussionmentioning

confidence: 99%

A Novel Truncating LMNA Mutation in Patients with Cardiac Conduction Disorders and Dilated Cardiomyopathy

et al. 2018

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“…Since Bonne et al identified the first LMNA gene mutation in patients affected with autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD), dilated cardiomyopathy (DCM) and conduction defects in 1999 [27], mutations in LMNA have subsequently been identified in individuals with isolated DCM, usually with a conduction defect [28]. Atrial or ventricular arrhythmias are often present and even precede the onset of DCM [28-33]. The heterogeneity of LMNA mutations was further established by the lack of clear genotype-phenotype correlations [26,34].…”

Section: Discussionmentioning

confidence: 99%

Whole-Exome Sequencing to Identify a Novel LMNA Gene Mutation Associated with Inherited Cardiac Conduction Disease

et al. 2013

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BackgroundInherited cardiac conduction diseases (CCD) are rare but are caused by mutations in a myriad of genes. Recently, whole-exome sequencing has successfully led to the identification of causal mutations for rare monogenic Mendelian diseases.ObjectiveTo investigate the genetic background of a family affected by inherited CCD.Methods and ResultsWe used whole-exome sequencing to study a Chinese family with multiple family members affected by CCD. Using the pedigree information, we proposed a heterozygous missense mutation (c.G695T, Gly232Val) in the lamin A/C (LMNA) gene as a candidate mutation for susceptibility to CCD in this family. The mutation is novel and is expected to affect the conformation of the coiled-coil rod domain of LMNA according to a structural model prediction. Its pathogenicity in lamina instability was further verified by expressing the mutation in a cellular model.ConclusionsOur results suggest that whole-exome sequencing is a feasible approach to identifying the candidate genes underlying inherited conduction diseases.

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“…(Kochanek et al, 2011;Xu et al, 2010). Various types of heart diseases from the most common atrial fibrillation to the lethal sudden cardiac death have been associated with pacemaker defects (Marsman et al, 2011;Tsai et al, 2000). Recent studies have established a casual relationship between certain genetic defects and SAN abnormalities, though the genetic regulatory network is still not well understood (Aanhaanen et al, 2011;Puskaric et al, 2010).…”

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confidence: 99%

Generation of Shox2‐Cre allele for tissue specific manipulation of genes in the developing heart, palate, and limb

Sun

Zhang

Liu

et al. 2013

Genesis

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Shox2 is expressed in several developing organs in a tissue specific manner in both mice and humans, including the heart, palate, limb, and nervous system. To better understand the spatial and temporal expression patterns of Shox2 and to systematically dissect the genetic cascade regulated by Shox2, we created Shox2-LacZ and Shox2-Cre knock-in mouse lines. We show that the Shox2-LacZ allele expresses beta-galactosidase reporter gene in a fashion that recapitulates the endogenous Shox2 expression pattern in developing organs, including the sinoatrial node (SAN), the anterior portion of the palate, and the proximal region of the limb bud. Conditional deletion of Shox2 in mice carrying the Shox2-Cre allele yielded SAN phenotypes that resemble conventional Shox2 knockout mice. Our results indicate that the Shox2-Cre allele offer a useful tool for tissue specific manipulation of genes in a number of developing organs, particularly in the developing SAN.

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A Complex Double Deletion in LMNA Underlies Progressive Cardiac Conduction Disease, Atrial Arrhythmias, and Sudden Death

Cited by 24 publications

References 45 publications

A Novel Truncating <i>LMNA</i> Mutation in Patients with Cardiac Conduction Disorders and Dilated Cardiomyopathy

A Novel Truncating <i>LMNA</i> Mutation in Patients with Cardiac Conduction Disorders and Dilated Cardiomyopathy

Whole-Exome Sequencing to Identify a Novel LMNA Gene Mutation Associated with Inherited Cardiac Conduction Disease

Generation of Shox2‐Cre allele for tissue specific manipulation of genes in the developing heart, palate, and limb

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