Université Côte d'Azur, Nice Teaching Hospital (CHU de Nice), Department of Medical Genetics, National Centre for Mitochondrial Diseases, Nice, France; Université Côte d'Azur, CNRS, INSERM, IRCAN, Nice, France.
Marseille Teaching Hospital, La Conception hospital, Department of Internal Medicine, Marseille, France.
Eur J Med Genet. 2022 Dec;65(12):104643. doi: 10.1016/j.ejmg.2022.104643. Epub 2022 Oct 14.
Biallelic rare variants in NARS2 that encode the mitochondrial asparaginyl-tRNA synthetase are associated with a wide spectrum of clinical phenotypes ranging from severe neurodegenerative disorders to isolated mitochondrial myopathy or deafness. To date, only a small number of patients with NARS2 variants have been reported, and possible genotype-phenotype correlations are still lacking. Here, we present three siblings who had an early-onset hearing loss, while one developed severe symptoms in adulthood associated with early intellectual impairment, refractory seizures, moderate axonal sensorimotor neuropathy, and atypical psychiatric symptoms. Biochemical analysis revealed impairment of the activity and assembly of the respiratory chain complexes in this patient's muscle and fibroblasts. Whole Exome Sequencing allowed identification of a heterozygous variant NM_024678.5(NARS2):c.822G > C (p.Gln274His) that is known to be pathogenic and to affect splicing of the NARS2 gene, but was unable to detect a second variant in this gene. Coverage analysis and Sanger sequencing led to identification of a novel intronic deletion NM_024678.5(NARS2):c.922-21_922-19del in the three siblings in trans with the c.822G > C. Functional analysis by RT-PCR showed that this deletion was causing aberrant splicing and led to exon 9 skipping in NARS2 mRNA in patient fibroblasts. Our work expands the phenotype and genotype spectrum of NARS2-related disorders. We provide evidence of the pathogenic effect of a novel intronic deletion in the NARS2 gene and report on additional adult patients with a large intrafamilial variability associated with splice variants in this gene. More specifically, we detail the phenotype of the oldest living patient to date with NARS2 variants and, for the first time, we report the psychiatric symptoms associated with this gene. Our work confirms the complexity of genotype-phenotype correlation in patients with pathogenic NARS2 variants.
NARS2 中的双等位基因罕见变异，这些变异编码线粒体天冬酰胺-tRNA 合成酶，与从严重神经退行性疾病到孤立性线粒体肌病或耳聋的广泛临床表型谱相关。迄今为止，仅报道了少数 NARS2 变异患者，并且仍然缺乏可能的基因型-表型相关性。在这里，我们介绍了三个兄弟姐妹，他们都患有早发性听力损失，而其中一个在成年后出现了严重的症状，伴有早期智力障碍、难治性癫痫发作、中度轴索性感觉运动神经病和非典型精神病症状。生化分析显示，该患者的肌肉和成纤维细胞中的呼吸链复合物的活性和组装受到损害。全外显子组测序鉴定出杂合变异 NM_024678.5(NARS2):c.822G>C(p.Gln274His)，已知该变异是致病性的，并且影响 NARS2 基因的剪接，但未能在该基因中检测到第二个变异。覆盖分析和 Sanger 测序导致在三个兄弟姐妹中鉴定出 NM_024678.5(NARS2):c.922-21_922-19del 的新内含子缺失，与 c.822G>C 呈反式。通过 RT-PCR 进行的功能分析表明，该缺失导致异常剪接，并导致 NARS2 mRNA 中exon 9 跳跃。我们的工作扩展了 NARS2 相关疾病的表型和基因型谱。我们提供了 NARS2 基因中新的内含子缺失的致病作用证据，并报告了该基因中的剪接变异与另外成年患者的大型家族内变异性相关的附加成年患者。更具体地，我们详细描述了迄今为止患有 NARS2 变异的最年长存活患者的表型，并且首次报告了与该基因相关的精神病症状。我们的工作证实了致病性 NARS2 变异患者的基因型-表型相关性的复杂性。
