Translating genetic and functional data into clinical practice: a series of 223 families with myotonia.
Translating genetic and functional data into clinical practice: a series of 223 families with myotonia.
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DOI：
10.1093/brain/awab344
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发表时间：
2022-04-18
期刊：
影响因子：
14.5
通讯作者：
Mannikko, Roope
中科院分区：
文献类型：
--
作者：
Suetterlin, Karen;Matthews, Emma;Sud, Richa;McCall, Samuel;Fialho, Doreen;Burge, James;Jayaseelan, Dipa;Haworth, Andrea;Sweeney, Mary G.;Kullmann, Dimitri M.;Schorge, Stephanie;Hanna, Michael G.;Mannikko, Roope
高通量DNA测序越来越多地用于诊断单基因神经和神经肌肉疾病。大量的数据对数据的解释以及将其有效地转化为家庭的临床和遗传咨询提出了新的挑战。即使当一个合理的基因被确定的信心，解释的临床意义和遗传模式的变异可能是具有挑战性的。我们报告了我们的方法来评估骨骼肌氯离子通道ClC-1的变异体，这些变异体在223例先天性肌强直先证者中鉴定，作为这些挑战的一个例子。CLCN 1基因编码的CLC-1的测序是诊断先天性肌强直的关键。然而，解释新变体的致病性和遗传模式是非常困难的，因为在整个通道序列中报告了显性和隐性突变，ClC-1结构-功能知之甚少，并且报告了表型的显著家族内和家族间变异性。广泛报道了用于研究CIC-1变体的功能后果的异源表达系统，以帮助评估致病性和遗传模式。然而，异质性的报告分析不允许系统的相关性，可用的功能和遗传数据。我们报告了223名先证者中95种CIC-1变异的系统评价，这是最大的报告患者队列，我们应用标准化功能分析并将其与临床评估和遗传模式相关联。这种相关性对于确定功能数据是否提高了变异解释的准确性和可能的遗传模式是重要的。我们的数据提供了一种循证方法，即ClC-1变体的功能表征改善了其致病性和遗传模式的临床解释，并作为34个以前未报道和28个以前未表征的CLCN 1变体的参考。此外，我们确定了新的致病机制，并发现改变电压依赖性的激活簇的跨膜结构域的前半部分和不产生电流簇的跨膜结构域的后半部分的变体。胞内结构域的变异与先天性肌强直的显性功能特征或显性遗传模式无关。我们的数据有助于根据新变异的位置对预期的遗传模式进行初步估计，并表明系统的功能表征可以显着改善相关遗传模式的风险评估，从而改善临床和遗传咨询。Suetterlin等人对骨骼肌氯离子通道ClC-1的95个错义变体进行了功能分析，并将数据与223个肌强直家族的遗传模式和临床表型相关联。这些发现为改善肌强直患者的遗传咨询提供了循证指南。
High-throughput DNA sequencing is increasingly employed to diagnose single gene neurological and neuromuscular disorders. Large volumes of data present new challenges in data interpretation and its useful translation into clinical and genetic counselling for families. Even when a plausible gene is identified with confidence, interpretation of the clinical significance and inheritance pattern of variants can be challenging. We report our approach to evaluating variants in the skeletal muscle chloride channel ClC-1 identified in 223 probands with myotonia congenita as an example of these challenges. Sequencing of CLCN1, the gene that encodes CLC-1, is central to the diagnosis of myotonia congenita. However, interpreting the pathogenicity and inheritance pattern of novel variants is notoriously difficult as both dominant and recessive mutations are reported throughout the channel sequence, ClC-1 structure-function is poorly understood and significant intra- and interfamilial variability in phenotype is reported. Heterologous expression systems to study functional consequences of CIC-1 variants are widely reported to aid the assessment of pathogenicity and inheritance pattern. However, heterogeneity of reported analyses does not allow for the systematic correlation of available functional and genetic data. We report the systematic evaluation of 95 CIC-1 variants in 223 probands, the largest reported patient cohort, in which we apply standardized functional analyses and correlate this with clinical assessment and inheritance pattern. Such correlation is important to determine whether functional data improves the accuracy of variant interpretation and likely mode of inheritance. Our data provide an evidence-based approach that functional characterization of ClC-1 variants improves clinical interpretation of their pathogenicity and inheritance pattern, and serve as reference for 34 previously unreported and 28 previously uncharacterized CLCN1 variants. In addition, we identify novel pathogenic mechanisms and find that variants that alter voltage dependence of activation cluster in the first half of the transmembrane domains and variants that yield no currents cluster in the second half of the transmembrane domain. None of the variants in the intracellular domains were associated with dominant functional features or dominant inheritance pattern of myotonia congenita. Our data help provide an initial estimate of the anticipated inheritance pattern based on the location of a novel variant and shows that systematic functional characterization can significantly refine the assessment of risk of an associated inheritance pattern and consequently the clinical and genetic counselling. Suetterlin et al. perform functional analyses of 95 missense variants of skeletal muscle chloride channel ClC-1, and correlate the data with mode of inheritance and clinical phenotype in 223 families with myotonia. The findings provide an evidence-based guide for improved genetic counselling of patients with myotonia.
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