Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy.
Folkhälsan Research Center, Helsinki, Uusimaa, Finland.
Ann Clin Transl Neurol. 2024 Oct;11(10):2745-2755. doi: 10.1002/acn3.52189. Epub 2024 Aug 28.
Biallelic titin truncating variants (TTNtv) have been associated with a wide phenotypic spectrum, ranging from complex prenatal muscle diseases with dysmorphic features to adult-onset limb-girdle muscular dystrophy, with or without cardiac involvement. Given the size and complexity of TTN, reaching an unequivocal molecular diagnosis and precise disease prognosis remains challenging.
In this case series, 12 unpublished cases and one already published case with biallelic TTNtv were collected from multiple international medical centers between November 2022 and September 2023. TTN mutations were detected through exome or genome sequencing. Information about familial and personal clinical history was collected in a standardized form. RNA-sequencing and analysis of TTN exon usage were performed on an internal sample cohort including postnatal skeletal muscles, fetal skeletal muscles, postnatal heart muscles, and fetal heart muscles. In addition, publicly available RNA-sequencing data was retrieved from ENCODE.
We generated new RNA-seq data on TTN exons and identified genotype-phenotype correlations with prognostic implications for each titinopathy patient (whether worsening or improving in prenatal and postnatal life) using percentage spliced in (PSI) data for the involved exons. Interestingly, thanks to exon usage, we were also able to rule out a titinopathy diagnosis in one prenatal case.
This study demonstrates that exon usage provides valuable insights for a more exhaustive clinical interpretation of TTNtv; additionally, it may serve as a model for implementing personalized medicine in many other genetic diseases, since most genes undergo alternative splicing.
双等位基因肌联蛋白截断变异（TTNtv）与广泛的表型谱相关，从伴有畸形特征的复杂产前肌肉疾病到伴或不伴心脏受累的成人起病的肢带型肌营养不良症不等。鉴于 TTN 的大小和复杂性，明确的分子诊断和精确的疾病预后仍然具有挑战性。
在本病例系列中，于 2022 年 11 月至 2023 年 9 月期间，从多个国际医学中心收集了 12 例未发表的病例和 1 例已发表的双等位基因 TTNtv 病例。通过外显子组或基因组测序检测 TTN 突变。通过标准化表格收集关于家族和个人临床病史的信息。对包括产后骨骼肌、胎儿骨骼肌、产后心肌和胎儿心肌在内的内部样本队列进行 TTN 外显子使用的 RNA 测序和分析。此外，还从 ENCODE 检索了公开可用的 RNA 测序数据。
我们生成了 TTN 外显子的新 RNA-seq 数据，并使用涉及的外显子的百分比拼接（PSI）数据，根据每个肌联蛋白病患者（在产前和产后生活中是恶化还是改善）的基因型-表型相关性，为每个肌联蛋白病患者生成了有预后意义的结果。有趣的是，由于外显子的使用，我们还能够排除一个产前病例的肌联蛋白病诊断。
本研究表明，外显子的使用为 TTNtv 的更详尽临床解释提供了有价值的见解；此外，它可以作为在许多其他遗传疾病中实施个体化医学的模型，因为大多数基因都经历可变剪接。
