Introduction Arthrogryposis is characterized by the presence of multiple contractures at birth and can be caused by pathogenic variants in TTN (Titin). Exons and variants that are not expressed in one of the three major isoforms of titin are referred to as “metatranscript-only” and have been considered to be only expressed during fetal development. Recently, the metatranscript-only variant (c.39974–11T > G) in TTN with a second truncating TTN variant has been linked to arthrogryposis multiplex congenita and myopathy.

Methods Via exome sequencing we identified the TTN c.39974–11T > G splice variant in trans with one of three truncating variants (p.Arg8922*, p.Lys32998Asnfs*63, p.Tyr10345*) in five individuals from three families. Clinical presentation and muscle ultrasound as well as MRI images were analyzed.

Results All five patients presented with generalized muscular hypotonia, reduced muscle bulk, and congenital contractures most prominently affecting the upper limbs and distal joints. Muscular hypotonia persisted and contractures improved over time. One individual, the recipient twin in the setting of twin-to-twin transfusion syndrome, died from severe cardiac hypertrophy 1 day after birth. Ultrasound and MRI imaging studies revealed a recognizable pattern of muscle involvement with striking fibrofatty involvement of the hamstrings and calves, and relative sparing of the femoral adductors and anterior segment of the thighs.

Conclusion The recurrent TTN c.39974–11T > G variant consistently causes congenital arthrogryposis and persisting myopathy providing evidence that the metatranscript-only 213 to 217 exons impact muscle elasticity during early development and beyond. There is a recognizable pattern of muscle involvement, which is distinct from other myopathies and provides valuable clues for diagnostic work-up.

简介 关节弯曲症的特点是出生时存在多处挛缩，并且可能由TTN ( Titin ) 中的致病性变异引起。未在肌联蛋白的三种主要同种型之一中表达的外显子和变体被称为“仅元转录”，并被认为仅在胎儿发育期间表达。最近， TTN中的仅元转录变体 (c.39974–11T > G)与第二个截断TTN变体已与先天性多发性关节弯曲症和肌病有关。

方法 通过外显子组测序，我们在来自三个家族的五个个体中鉴定了TTN c.39974–11T > G反式剪接变体，其中具有三个截短变体（ p.Arg8922*、p.Lys32998Asnfs*63、p.Tyr10345*）之一。分析临床表现和肌肉超声以及MRI图像。

结果 所有 5 名患者均出现全身性肌张力减退、肌肉体积减少和先天性挛缩，最显着地影响上肢和远端关节。肌张力减退持续存在，挛缩随着时间的推移而改善。一个人，双胞胎输血综合征的接受双胞胎，在出生后 1 天死于严重的心脏肥大。超声和 MRI 成像研究显示肌肉受累的可识别模式，腘绳肌和小腿明显的纤维脂肪受累，股骨内收肌和大腿前段相对保留。

结论 复发性TTN c.39974–11T > G 变异始终导致先天性关节弯曲和持续性肌病，这提供了仅元转录的 213 至 217 个外显子在早期发育期间及以后影响肌肉弹性的证据。有一种可识别的肌肉受累模式，这与其他肌病不同，为诊断工作提供了有价值的线索。