患有肌联蛋白病的儿童中的双等位基因截短变异代表一种具有独特肌肉和心脏特征的可识别病症：五例患者报告

Biallelic truncating variants in children with titinopathy represent a recognizable condition with distinctive muscular and cardiac characteristics: a report on five patients.

作者信息

Baban Anwar, Cicenia Marianna, Magliozzi Monia, Parlapiano Giovanni, Cirillo Marco, Pascolini Giulia, Fattori Fabiana, Gnazzo Maria, Bruno Pasqualina, De Luca Lorenzo, Di Chiara Luca, Francalanci Paola, Udd Bjarne, Secinaro Aurelio, Amodeo Antonio, Bertini Enrico Silvio, Savarese Marco, Drago Fabrizio, Novelli Antonio

机构信息

Pediatric Cardiology and Arrhythmia/Syncope Complex Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

出版信息

Front Cardiovasc Med. 2023 Jul 27;10:1210378. doi: 10.3389/fcvm.2023.1210378. eCollection 2023.

DOI:10.3389/fcvm.2023.1210378

PMID:37576110

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10415037/

Abstract

BACKGROUND

Monoallelic and biallelic truncating variants () may be responsible for a wide spectrum of musculoskeletal and cardiac disorders with different age at onset. Although the prevalence of heterozygous is relatively high in the general population, cardiac phenotyping (mainly cardiomyopathies, CMPs) in biallelic titinopathy has rarely been described in children.

METHODS

We reviewed the medical records of pediatric patients with biallelic and cardiac involvement. Clinical exome sequencing excluded pathogenic/likely pathogenic variants in major CMP genes.

RESULTS

Five pediatric patients (four male) with biallelic were included. Major arthrogryposis multiplex was observed in four patients; no patient showed intellectual disability. At a cardiac level, congenital heart defects (atrial and ventricular septal defects, = 3) and left ventricular non-compaction ( = 1) were reported. All patients had dilated cardiomyopathy (DCM) diagnosed at birth in one patient and at the age of 10, 13, 14, and 17 years in the other four patients. Heart rhythm monitoring showed tachyarrhythmias (premature ventricular contractions, = 2; non-sustained ventricular tachycardia, = 2) and nocturnal first-degree atrio-ventricular block ( = 2). Cardiac magnetic resonance (CMR) imaging was performed in all patients and revealed a peculiar late gadolinium enhancement distribution in three patients. HyperCKemia was present in two patients and end-stage heart failure in four. End-organ damage requiring heart transplantation (HT) was indicated in two patients, who were operated on successfully.

CONCLUSION

Biallelic should be considered when evaluating children with severe and early-onset DCM, particularly if skeletal and muscular abnormalities are present, e.g., arthrogryposis multiplex and congenital progressive myopathy. End-stage heart failure is common and may require HT.

摘要

背景

单等位基因和双等位基因截短变异（）可能导致多种不同发病年龄的肌肉骨骼和心脏疾病。尽管杂合子在普通人群中的患病率相对较高，但双等位基因肌联蛋白病患儿的心脏表型（主要是心肌病，CMPs）却鲜有描述。

方法

我们回顾了患有双等位基因且有心脏受累的儿科患者的病历。临床外显子组测序排除了主要CMP基因中的致病/可能致病变异。

结果

纳入了5例患有双等位基因的儿科患者（4例男性）。4例患者出现严重的多发性关节挛缩；无患者表现出智力残疾。在心脏方面，报告了先天性心脏缺陷（房间隔和室间隔缺损，n = 3）和左心室心肌致密化不全（n = 1）。所有患者均患有扩张型心肌病（DCM），1例患者在出生时被诊断出，另外4例患者分别在10岁、13岁、14岁和17岁时被诊断出。心律监测显示有室性心律失常（室性早搏，n = 2；非持续性室性心动过速，n = 2）和夜间一度房室传导阻滞（n = 2）。所有患者均进行了心脏磁共振（CMR）成像，3例患者显示出特殊的钆延迟强化分布。2例患者出现高肌酸激酶血症，4例患者出现终末期心力衰竭。2例患者出现需要心脏移植（HT）的终末器官损害，并成功接受了手术。