Genetic landscape of congenital insensitivity to pain and hereditary sensory and autonomic neuropathies.
Genetic landscape of congenital insensitivity to pain and hereditary sensory and autonomic neuropathies.
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DOI：
10.1093/brain/awad328
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发表时间：
2023-12-01
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先天性疼痛不敏感症（CIP）和遗传性感觉和自主神经病变（HSAN）是临床和遗传异质性疾病，专门或主要影响感觉和自主神经元。由于疾病的罕见性和主要基于单个病例报告或小病例系列的发现，有关这些疾病的知识是有限的。在这里，我们描述了一个大型国际队列的CIP/HSAN患者的分子检查，包括通常代表性不足的国家的患者。我们在超过20个已知的CIP/HSAN相关基因中，在总共73个家族中鉴定了80个以前未报道的致病性或可能致病性变体。这些数据扩大了CIP/HSAN中疾病相关改变的范围，包括以前很少识别的实体中的新变体，如ATL 3-，FLVCR 1-和NGF相关神经病变以及以前未被识别的突变类型，如较大的缺失。计算机模拟预测、异源表达研究、分离分析和代谢测试有助于克服当前变体分类方案的局限性，这些方案通常无法将变体分类为疾病相关或良性。这项研究揭示了CIP/HSAN中单个基因的遗传原因和疾病相关变化。随着研究亚型或基因特异性治疗策略的新兴临床试验的出现，这变得越来越重要。Lischka等人描述了对患有先天性疼痛不敏感/遗传性感觉和自主神经病变的大型患者队列的分子检查。他们在73个家族中确定了80种以前未报告的致病或可能致病的变异，扩大了这些罕见疾病的已知突变谱。
Congenital insensitivity to pain (CIP) and hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders exclusively or predominantly affecting the sensory and autonomic neurons. Due to the rarity of the diseases and findings based mainly on single case reports or small case series, knowledge about these disorders is limited. Here, we describe the molecular workup of a large international cohort of CIP/HSAN patients including patients from normally under-represented countries. We identify 80 previously unreported pathogenic or likely pathogenic variants in a total of 73 families in the >20 known CIP/HSAN-associated genes. The data expand the spectrum of disease-relevant alterations in CIP/HSAN, including novel variants in previously rarely recognized entities such as ATL3-, FLVCR1- and NGF-associated neuropathies and previously under-recognized mutation types such as larger deletions. In silico predictions, heterologous expression studies, segregation analyses and metabolic tests helped to overcome limitations of current variant classification schemes that often fail to categorize a variant as disease-related or benign. The study sheds light on the genetic causes and disease-relevant changes within individual genes in CIP/HSAN. This is becoming increasingly important with emerging clinical trials investigating subtype or gene-specific treatment strategies. Lischka et al. describe the molecular workup of a large cohort of patients with congenital insensitivity to pain/hereditary sensory and autonomic neuropathies. They identify 80 previously unreported pathogenic or likely pathogenic variants in 73 families, broadening the known mutational spectrum of these rare conditions.
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