Next generation sequencing (NGS) has allowed the titin gene (TTN) to be identified as a major contributor to neuromuscular disorders, with high clinical heterogeneity. The mechanisms underlying the phenotypic variability and the dominant or recessive pattern of inheritance are unclear. Titin is involved in the formation and stability of the sarcomeres. The effects of the different TTN variants can be harmless or pathogenic (recessive or dominant) but the interpretation is tricky because the current bioinformatics tools can not predict their functional impact. Moreover, TTN variants are very frequent in the general population. The combination of deep phenotyping associated with RNA molecular analyses, western blot (WB) and functional studies is often essential for the interpretation of genetic variants in patients suspected of titinopathy. In line with the current guidelines and suggestions, we implemented for patients with skeletal myopathy and with potentially disease causing TTN variant(s) an integrated genotype-transcripts-protein-phenotype approach, associated with phenotype and variants segregation studies in relatives and confrontation with published data on titinopathies to evaluate pathogenic effects of TTN variants (even truncating ones) on titin transcripts, amount, size and functionality. We illustrate this integrated approach in four patients with recessive congenital myopathy.

中文翻译：

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整合基因型 - 表型策略对解开钛白蛋白病分子基础的重要性

下一代测序 (NGS) 使肌联蛋白基因 (TTN) 被确定为神经肌肉疾病的主要因素，具有高度的临床异质性。表型变异性和显性或隐性遗传模式的潜在机制尚不清楚。肌联蛋白参与肌节的形成和稳定。不同 TTN 变异的影响可能是无害的或致病的（隐性或显性），但解释很棘手，因为当前的生物信息学工具无法预测它们的功能影响。此外，TTN 变异在一般人群中非常常见。与 RNA 分子分析、蛋白质印迹 (WB) 和功能研究相关的深层表型的组合对于解释疑似肌动蛋白病患者的遗传变异通常是必不可少的。根据当前的指南和建议，我们为骨骼肌病患者和可能导致 TTN 变异的患者实施了一种综合的基因型-转录物-蛋白质-表型方法，与亲属中的表型和变异分离研究以及与已发表的关于titinpathies的数据，以评估TTN变异（甚至截短的）对titin转录本、数量、大小和功能的致病作用。我们在四名隐性先天性肌病患者中说明了这种综合方法。与亲属中的表型和变异分离研究相关，并与已发表的关于肌动蛋白病的数据对峙，以评估 TTN 变体（甚至截断型）对肌动蛋白转录本、数量、大小和功能的致病作用。我们在四名隐性先天性肌病患者中说明了这种综合方法。与亲属中的表型和变异分离研究相关，并与已发表的关于肌动蛋白病的数据对峙，以评估 TTN 变体（甚至截断型）对肌动蛋白转录本、数量、大小和功能的致病作用。我们在四名隐性先天性肌病患者中说明了这种综合方法。