Pathogenic variants in TNNT3, the gene encoding fast skeletal muscle troponin T, were first described in autosomal dominant distal arthrogryposis type 2B2. Recently, a homozygous splice site variant, c.681+1G>A, was identified in a patient with nemaline myopathy and distal arthrogryposis. Here, we describe the second individual with congenital myopathy associated with biallelic TNNT3 variants.

Clinical exome sequencing data from a patient with molecularly undiagnosed congenital myopathy underwent research reanalysis. Clinical and histopathologic data were collected and compared with the single reported patient with TNNT3-related congenital myopathy.

A homozygous TNNT3 variant, c.481-1G>A, was identified. This variant alters a consensus splice acceptor and is predicted to affect splicing by multiple in silico prediction tools. Both the patient reported here and the previously published patient exhibited limb, bulbar, and respiratory muscle weakness from birth, which improved over time. Other shared features include history of polyhydramnios, hypotonia, scoliosis, and high-arched palate. Distal arthrogryposis and nemaline rods, findings reported in the first patient with TNNT3-related congenital myopathy, were not observed in the patient reported here.

This report provides further evidence for the association of biallelic TNNT3 variants with severe recessive congenital myopathy with or without nemaline rods and distal arthrogryposis. TNNT3 sequencing and copy number analysis should be incorporated into the workup of congenital myopathies.

TNNT3的致病性变异是编码快速骨骼肌肌钙蛋白 T 的基因，首先在常染色体显性远端关节弯曲 2B2 型中被描述。最近，在患有线虫肌病和远端关节弯曲的患者中发现了一个纯合剪接位点变异，c.681+1G>A。在这里，我们描述了第二个患有与双等位基因TNNT3变体相关的先天性肌病的个体。

来自一名分子未确诊的先天性肌病患者的临床外显子组测序数据进行了研究再分析。收集临床和组织病理学数据，并与单个报告的TNNT3相关先天性肌病患者进行比较。

鉴定了纯合TNNT3变体 c.481-1G>A。该变体改变了共有剪接受体，并且预计会通过多种计算机预测工具影响剪接。此处报告的患者和之前发表的患者在出生时都表现出肢体、延髓和呼吸肌无力，随着时间的推移，这种情况有所改善。其他共同特征包括羊水过多、张力减退、脊柱侧弯和高弓腭病史。在这里报告的患者中没有观察到远端关节弯曲和线虫棒，这是在第一例TNNT3相关先天性肌病患者中报告的发现。

该报告为双等位基因TNNT3变异与严重隐性先天性肌病（伴或不伴线虫棒和远端关节弯曲）之间的关联提供了进一步的证据。TNNT3测序和拷贝数分析应纳入先天性肌病的检查。