Aix Marseille University, INSERM, Marseille Medical Genetics, U1251 Marseille, France.
Department of Paediatric and Congenital Cardiology, Timone Hospital Marseille, University Hospital, 13005 Marseille, France.
Int J Mol Sci. 2022 May 6;23(9):5205. doi: 10.3390/ijms23095205.
Left Ventricular Non-Compaction (LVNC) is defined by the triad prominent myocardial trabecular meshwork, thin compacted layer, and deep intertrabecular recesses. LVNC associated with dilation is characterized by the coexistence of left ventricular dilation and systolic dysfunction. Pediatric cases with dilated-LVNC have worse outcomes than those with isolated dilated cardiomyopathy and adult patients. Herein, we report a clinical and genetic investigation using trio-based whole-exome sequencing of a pediatric case with early-onset dilated-LVNC. Compound heterozygous mutations were identified in the Striated Muscle Enriched Protein Kinase () gene, a key regulator of cardiac calcium homeostasis. A paternally inherited mutation: ; p.(Arg2470Ser) and the second variant, ; p.(Pro2687Thr), is common and occurred de novo. Subsequently, Sanger sequencing was performed for the family in order to segregate the variants. Thus, the index case, his father, and both sisters carried the : p.(Arg2470Ser) variant. Only the index patient carried both variants. Both sisters, as well as the patient's father, showed LVNC without cardiac dysfunction. The unaffected mother did not harbor any of the variants. The in silico analysis of the identified variants (rare and common) showed a decrease in protein stability with alterations of the physical properties as well as high conservation scores for the mutated residues. Interestingly, using the Project HOPE tool, the ; p.(Pro2687Thr) variant is predicted to disturb the second fibronectin type III domain of the protein and may abolish its function. To our knowledge, the present case is the first description of compound heterozygous mutations involving a de novo variant and causing dilated-LVNC without neuropathy or centronuclear myopathy.
左心室心肌致密化不全（LVNC）的定义为心肌小梁网格结构明显、致密化层薄和深小梁间陷窝。与扩张相关的 LVNC 以左心室扩张和收缩功能障碍共存为特征。伴有扩张的儿科 LVNC 病例的预后比孤立性扩张型心肌病和成年患者差。在此，我们报告了一例使用基于三亲体的全外显子组测序进行的儿科早发性扩张型 LVNC 的临床和遗传学研究。在 Striated Muscle Enriched Protein Kinase () 基因中发现了复合杂合突变，该基因是心脏钙稳态的关键调节因子。一个父系遗传的突变：；p.(Arg2470Ser)和第二个变体；p.(Pro2687Thr)是常见的，并发生在新生突变中。随后，对家系进行 Sanger 测序以分离变体。因此，索引病例、他的父亲和两个姐妹都携带：p.(Arg2470Ser)变体。只有索引患者携带这两种变体。两个姐妹以及患者的父亲都表现出 LVNC 但没有心脏功能障碍。未受影响的母亲没有携带任何变体。对鉴定出的变体（罕见和常见）的计算机分析显示，蛋白质稳定性降低，物理特性发生变化，突变残基的保守评分高。有趣的是，使用 Project HOPE 工具，；p.(Pro2687Thr)变体被预测会干扰蛋白的第二个纤维连接蛋白 III 结构域，并可能使其功能丧失。据我们所知，目前的病例是第一个描述涉及新生变体的复合杂合 突变并导致无神经病或中心核肌病的扩张型 LVNC 的病例。
