目标:在下一代测序(NGS)之前,对神经病变患者的评估通常包括筛查获得性原因,然后对50岁之前有阳性家族史和症状发作的患者进行PMP22,MFN2,GJB1和MPZ的临床基因检测.在这项研究中,我们在商业实验室分析的大量患者队列中检查了NGS的临床应用.
方法:一组6849名成年患者接受了临床医生订购的周围神经病变多基因小组测试,范围为66至111个基因,包括NGS和基因内缺失/重复分析。
结果:对8.4%的队列(n=573/6849)进行了分子诊断。PMP22,MFN2,GJB1,MPZ,TTR占分子诊断的73.8%。结果对398例(69.5%)患者具有潜在的临床可操作性。我们的结果表明,如果测试方法仅限于较旧的指南,则可能会错过225/573(39.3%)的分子诊断和113/398(28.4%)的临床干预措施。
结论:我们的研究结果强调需要扩大基因检测指南,以解释与遗传性神经病相关的基因数量的增加,解决获得性和遗传性神经病的重叠问题,并为患者提供更广泛的基因诊断。
OBJECTIVE: Prior to next-generation sequencing (NGS), the evaluation of a patient with
neuropathy typically consisted of screening for acquired causes, followed by clinical genetic testing of PMP22, MFN2, GJB1, and MPZ in patients with a positive family history and symptom onset prior to age 50. In this study, we examined the clinical utility of NGS in a large cohort of patients analyzed in a commercial laboratory.
METHODS: A cohort of 6849 adult patients underwent clinician-ordered peripheral
neuropathy multigene panel testing ranging from 66 to 111 genes that included NGS and intragenic deletion/duplication analysis.
RESULTS: A molecular diagnosis was identified for 8.4% of the cohort (n = 573/6849). Variants in PMP22, MFN2, GJB1, MPZ, and TTR accounted for 73.8% of molecular diagnoses. Results had potential clinical actionability for 398 (69.5%) patients. Our results suggest that 225/573 (39.3%) of molecular diagnoses and 113/398 (28.4%) of clinical interventions would have been missed if the testing approach had been restricted to older guidelines.
CONCLUSIONS: Our results highlight the need for expanded genetic testing guidelines that account for the increased number of genes associated with hereditary
neuropathy, address the overlap of acquired and hereditary
neuropathy, and provide broader access to genetic diagnosis for patients.