Li Shuyuan, Hua Renyi, Han Xu, Xu Yan, Li Ming, Gao Li, Ma Ruiyu, Meng Wanli, Mao Aiping, Wang Jian, Wang Yanlin
International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, 910 Hengshan Road, Shanghai, 200030, China.
Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, China.
J Transl Med. 2025 Mar 11;23(1):307. doi: 10.1186/s12967-025-06345-1.
Next-generation sequencing (NGS) has been applied for carrier screening, effectively reducing the incidence of severe diseases. However, some severe, high-prevalent and complex diseases, including spinal muscular atrophy (SMA), α-/β-thalassemia, 21-hydroxylase deficiency (21-OHD), and fragile-X syndrome (FXS), cannot be fully addressed by NGS, resulting in a high residual risk ratio. This study aims to evaluate the clinical utility of a long-read sequencing (LRS) panel for carrier screening of these five complex diseases.
A total of 2926 participants were retrospectively enrolled from International Peace Maternity and Child Health Hospital from Jan 2019 to Dec 2022. All the participants were previously screened for 149 genes correlated to 147 diseases by NGS. The samples were collected and analyzed with the LRS panel targeting the five complex diseases.
LRS identified 236 carrier variants, including 54 for SMA, 113 for α-thalassemia, 19 for β-thalassemia, 47 for 21-OHD, and three for FXS. NGS identified only 56.4% (133/236) of the variants detected by LRS. NGS failed to detect three SMA carriers with SMN1 intragenic variants, while reported 10 false-positive carriers for α-thalassemia (HKαα miscalled as -α3.7). Both 21-OHD and FXS were beyond its detection scope. NGS identified only three of the seven at-risk couples determined by LRS. The total estimated at-risk couple rate for 151 genes in NGS and LRS panels was 1.0996%. SMA, α-/β-thalassemia, 21-OHD, and FXS were among the top 30 high-prevalent diseases and had a combined at-risk couple rate of 0.2433%, accounting for 22.1% of the total ratio. NGS could only identify 22.7% of the at-risk couples for the five diseases in the LRS panel.
Comprehensive carrier screening for high-prevalent diseases had higher clinical utility than expanding the list of low-prevalent diseases. Incorporating LRS into the NGS carrier screening strategy would facilitate more effective carrier screening.
下一代测序（NGS）已应用于携带者筛查，有效降低了严重疾病的发病率。然而，一些严重、高发性和复杂性疾病，包括脊髓性肌萎缩症（SMA）、α/β地中海贫血、21-羟化酶缺乏症（21-OHD）和脆性X综合征（FXS），不能通过NGS完全解决，导致残留风险率较高。本研究旨在评估长读长测序（LRS） panel对这五种复杂疾病进行携带者筛查的临床效用。
回顾性纳入2019年1月至2022年12月在国际和平妇幼保健院的2926名参与者。所有参与者此前已通过NGS对与147种疾病相关的149个基因进行了筛查。收集样本并用针对这五种复杂疾病的LRS panel进行分析。
LRS鉴定出236个携带者变异，其中SMA有54个，α地中海贫血有113个，β地中海贫血有19个，21-OHD有47个，FXS有3个。NGS仅鉴定出LRS检测到的变异的56.4%（133/236）。NGS未能检测到3名携带SMN1基因内变异的SMA携带者，同时报告了10名α地中海贫血的假阳性携带者（HKαα误称为-α3.7）。21-OHD和FXS均超出其检测范围。NGS仅鉴定出LRS确定的7对高危夫妇中的3对。NGS和LRS panel中151个基因的总估计高危夫妇率为1.0996%。SMA、α/β地中海贫血、21-OHD和FXS属于前30种高发性疾病，综合高危夫妇率为0.2433%，占总比例的22.1%。NGS只能鉴定出LRS panel中五种疾病的22.7%的高危夫妇。
对高发性疾病进行全面的携带者筛查比扩大低发性疾病列表具有更高的临床效用。将LRS纳入NGS携带者筛查策略将有助于更有效地进行携带者筛查。
