Dilated cardiomyopathy (DCM) belongs to the most frequent forms of cardiomyopathy mainly characterized by cardiac dilatation and reduced systolic function. Although most cases of DCM are classified as sporadic, 20–30% of cases show a heritable pattern. Familial forms of DCM are genetically heterogeneous, and mutations in several genes have been identified that most commonly play a role in cytoskeleton and sarcomere-associated processes. Still, a large number of familial cases remain unsolved. Here, we report five individuals from three independent families who presented with severe dilated cardiomyopathy during the neonatal period. Using whole-exome sequencing (WES), we identified causative, compound heterozygous missense variants in RPL3L (ribosomal protein L3-like) in all the affected individuals. The identified variants co-segregated with the disease in each of the three families and were absent or very rare in the human population, in line with an autosomal recessive inheritance pattern. They are located within the conserved RPL3 domain of the protein and were classified as deleterious by several in silico prediction software applications. RPL3L is one of the four non-canonical riboprotein genes and it encodes the 60S ribosomal protein L3-like protein that is highly expressed only in cardiac and skeletal muscle. Three-dimensional homology modeling and in silico analysis of the affected residues in RPL3L indicate that the identified changes specifically alter the interaction of RPL3L with the RNA components of the 60S ribosomal subunit and thus destabilize its binding to the 60S subunit. In conclusion, we report that bi-allelic pathogenic variants in RPL3L are causative of an early-onset, severe neonatal form of dilated cardiomyopathy, and we show for the first time that cytoplasmic ribosomal proteins are involved in the pathogenesis of non-syndromic cardiomyopathies.

扩张型心肌病 (DCM) 属于最常见的心肌病形式，主要以心脏扩张和收缩功能降低为特征。尽管大多数 DCM 病例被归类为散发性，但 20-30% 的病例显示出可遗传模式。DCM 的家族形式在遗传上是异质的，并且已经确定了几个基因的突变，这些突变最常在细胞骨架和肌节相关过程中发挥作用。尽管如此，仍有大量家庭案件尚未解决。在这里，我们报告了来自三个独立家庭的五个人，他们在新生儿期出现了严重的扩张型心肌病。使用全外显子组测序 (WES)，我们确定了RPL3L中的致病复合杂合错义变体（核糖体蛋白 L3 样）在所有受影响的个体中。鉴定出的变异在三个家族的每一个中都与疾病共同分离，并且在人群中不存在或非常罕见，这与常染色体隐性遗传模式一致。它们位于蛋白质的保守 RPL3 结构域内，并被几个计算机预测软件应用程序归类为有害。RPL3L是四种非经典核糖蛋白基因之一，它编码仅在心肌和骨骼肌中高度表达的 60S 核糖体蛋白 L3 样蛋白。三维同源建模和计算机模拟对 RPL3L 中受影响残基的分析表明，已确定的变化特异性地改变了 RPL3L 与 60S 核糖体亚基的 RNA 成分的相互作用，从而使其与 60S 亚基的结合不稳定。总之，我们报告RPL3L中的双等位基因致病变异是早发性严重新生儿扩张型心肌病的原因，并且我们首次表明细胞质核糖体蛋白参与了非综合征型心肌病的发病机制。