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Case Reports
. 2025 Sep;27(9):1788-1792.
doi: 10.1002/ejhf.3695. Epub 2025 May 24.

Genotype-guided cardiac device intervention in LMNA-related cardiac conduction disorder: The need for timely genetic testing

Shunsuke Inoue  1   2 , Zhehao Dai  1   2 , Tsukasa Oshima  1 , Seitaro Nomura  1   2 , Takashi Hiruma  1 , Ryo Abe  1 , Kanna Fujita  1   3 , Manami Katoh  1   2 , Toshiyuki Ko  1   2 , Yu Shimizu  1 , Masamichi Ito  1 , Kenichiro Yamagata  1 , Junichi Ishida  1 , Eisuke Amiya  1 , Masaru Hatano  1 , Norifumi Takeda  1   4 , Hiroyuki Morita  1 , Katsuhito Fujiu  1 , Norihiko Takeda  1 , Issei Komuro  2   5
Affiliations
Case Reports

Genotype-guided cardiac device intervention in LMNA-related cardiac conduction disorder: The need for timely genetic testing

Shunsuke Inoue et al. Eur J Heart Fail. 2025 Sep.
No abstract available

Keywords: Cardiac conduction disorder; Cardiomyopathy; Genetics; Laminopathy.

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Figures

Figure 1
Figure 1
Clinical and genetic characteristics of case no. 1. (A) The proband (III‐1; arrow) did not have family history of sudden cardiac death. His father (II‐2) was diagnosed with atrial flutter and received catheter ablation at the age of 47. Additionally, he was undertaken permanent pacemaker implantation at the age of 57. After these episodes, he has been free from any major cardiovascular adverse events. The proband's mother and younger brother (II‐1 and III‐2) had no cardiovascular disorder, during annual medical check‐ups. The proband's grandparents (I‐1 and 2) died of non‐cardiovascular diseases, traffic trauma and gastric cancer, respectively, at their 70s. As his family members living far away did not wish to be tested, only the proband underwent genetic testing in this family. Square, male; circle, female; arrow, proband; filled, arrhythmia; question mark, insufficient clinical information; slash line, died. (B and C) Electrocardiogram revealed atrial flutter with bradycardia and non‐sustained ventricular tachycardia. (D) Cardiac magnetic resonance imaging revealed no late gadolinium enhancement in the heart. (E) Electrocardiogram after the initial pacemaker implantation. Narrow QRS duration (92 ms) was achieved by left bundle branch area pacing. (F) Genetic testing using whole exome sequencing revealed a novel predicted loss‐of‐function LMNA variant (chr1:156136437(hg38), NM_170707.4, c.1380 + 1G>T), and the variant was confirmed using Sanger sequencing after 5 months from the initial surgery. As for this canonical splice donor site, a different nucleotide change (c.1380 + 1G>A) was previously reported to be pathogenic (ClinVar accession number: VCV000066817.13). Two different in‐silico scoring system predicted its pathogenicity (CADD score: 34, SpliceAI Δscore: 0.89). This variant was absent in the East Asian population in gnomAD. According to the current guidelines, we concluded this variant as pathogenic. (G) Eight months after the initial admission, he was readmitted and underwent the addition of a shock lead and an upgrade to cardiac resynchronization therapy with defibrillator. The right ventricular lead at the upper septum inserted in the first procedure was connected to the left ventricular lead connector port.
Figure 2
Figure 2
Clinical and genetic characteristics of case no. 2. (A) This male proband (III‐2; arrow) did not have family history of any cardiovascular disease or sudden cardiac death. His grandparents deceased in their 80–90s. His parents were in their 70s: his mother (II‐2) had a history of rheumatoid arthritis, but neither parent had any history of cardiovascular disease. His siblings were in their 40s, and except for the sister's type 2 diabetes, neither sibling had any notable medical history including any cardiovascular disease. (B and C) An electrocardiogram revealed Mobitz type 2 atrioventricular block and non‐sustained ventricular tachycardia. (D) Transthoracic echocardiogram showed reduced systolic dysfunction without left ventricular dilatation (left ventricular ejection fraction of 38% and global longitudinal strain of 14%, and left ventricular end‐diastolic diameter of 51 mm). No significant valvular disorder was detected. (E) Cardiac magnetic resonance images showed late gadolinium enhancement regions at the middle of interventricular septum (three red arrows). (F) Genetic testing via whole exome sequencing revealed a novel LMNA variant at the canonical splice donor site (chr1:156134530 (hg38), NM_170707.4, c.639 + 2 T>C), and the variant was confirmed using Sanger sequencing after 8 months from the initial surgery. Two different in‐silico scoring system predicted its pathogenicity (CADD score: 34, SpliceAI Δscore for splice loss: 0.85). This variant was absent in the East Asian population in gnomAD. (G) Results of prediction models for life‐threatening ventricular arrhythmia. MADIT‐ICD benefit score classified him as intermediate benefit group (risk of experiencing malignant arrhythmia at 3 years after implantable cardioverter‐defibrillator (ICD) implantation = 15% [13–17%] and risk of non‐arrhythmic death 3 years after ICD implantation = 9% [8–10%]). Prediction model for laminopathies estimated 5‐year risk of life‐threatening ventricular tachyarrhythmias as 64%. MVA, malignant ventricular arrhythmia.
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