To test the hypothesis that many patients presenting with congenital insensitivity to pain have lesser known or unidentified mutations not captured by conventional genetic panels, we performed whole-exome sequencing in a cohort of well-characterized patients with a clinical diagnosis of congenital hereditary sensory and autonomic neuropathy with unrevealing conventional genetic testing.

We performed whole-exome sequencing (WES) in 13 patients with congenital impaired or absent sensation to pain and temperature with no identified molecular diagnosis from a conventional genetic panel. Patients underwent a comprehensive phenotypic assessment including autonomic function testing, and neurologic and ophthalmologic examinations.

We identified known or likely pathogenic genetic causes of congenital insensitivity to pain in all 13 patients, spanning 9 genes, the vast majority of which were inherited in an autosomal recessive manner. These included known pathogenic variants (3 patients harboring mutations in TECPR2 and SCN11A), suspected pathogenic variants in genes described to cause congenital sensory and autonomic syndromes (7 patients harboring variants in NGF, LIFR, SCN9A, and PRDM12), and likely pathogenic variants in novel genes (4 patients harboring variants in SMPDL3A, PLEKHN1, and SCN10A).

Our results expand the genetic landscape of congenital sensory and autonomic neuropathies. Further validation of some identified variants should confirm their pathogenicity. WES should be clinically considered to expedite diagnosis, reduce laboratory investigations, and guide enrollment in future gene therapy trials.

为了验证以下假设，即许多先天性对疼痛不敏感的患者具有传统基因组无法捕获的鲜为人知或未识别的突变，我们在一组临床诊断为先天性遗传性感觉和自主神经的特征良好的患者中进行了全外显子组测序神经病与未揭示的传统基因检测。

我们对 13 名先天性疼痛和温度感觉受损或缺乏感觉的患者进行了全外显子组测序 (WES)，这些患者没有从常规基因组中确定分子诊断。患者接受了全面的表型评估，包括自主神经功能测试、神经系统和眼科检查。

我们确定了所有 13 名患者对疼痛先天性不敏感的已知或可能的致病性遗传原因，涉及 9 个基因，其中绝大多数以常染色体隐性方式遗传。这些包括已知的致病变异（3 名患者携带TECPR2和SCN11A突变），被描述为导致先天性感觉和自主神经综合征的基因中的疑似致病性变异（7 名患者携带NGF、LIFR、SCN9A和PRDM12的变异），以及可能在新基因（4 名患者携带SMPDL3A、PLEKHN1和SCN10A 变异）。

我们的研究结果扩展了先天性感觉和自主神经病的遗传景观。对一些已识别的变体的进一步验证应确认其致病性。临床上应考虑 WES 以加快诊断、减少实验室调查并指导未来基因治疗试验的招募。