Neonatal Disease Screening Center, Quanzhou Maternity and Children's Hospital, 700 Fengze Street, Quanzhou, 362000, Fujian Province, China.
Department of Neonatal Intensive Care Unit, Quanzhou Maternity and Children's Hospital, 700 Fengze Street, Quanzhou, 362000, Fujian Province, China.
Orphanet J Rare Dis. 2021 Mar 23;16(1):149. doi: 10.1186/s13023-021-01785-6.
Newborn screening for primary carnitine deficiency (NBS) is commonly implemented worldwide; however, it has poor sensitivity. This study aimed to evaluate the feasibility of improving screening by including a second-tier genetic assay.
An Agena iPLEX assay was developed to identify 17 common SLC22A5 mutations in Chinese populations and was applied in NBS as a second-tier screening. From January 2017 to December 2018, 204,777 newborns were screened for PCD using tandem mass spectrometry. A total of 316 (0.15%) residual NBS-positive specimens with low free carnitine (C0) levels were subjected to this second-tier screening. The screening identified 20 screen-positive newborns who harboured biallelic mutations in theSLC22A5 gene, 99 carriers with one mutation, and 197 screen-negative newborns with no mutations. Among the 99 carriers, four newborns were found to have a second disease-causing SLC22A5mutation by further genetic analysis. Among the 197 screen-negatives were four newborns with persistently low C0 levels, and further genetic analysis revealed that one newborn had two novel SLC22A5 pathogenic variants. In total, 25 newborns were diagnosed with PCD, for a positive predictive value of 7.91% (25/316). Based on these data, we estimate the incidence of PCD in Quanzhou is estimated to be 1:8191.Thirteen distinct SLC22A5 variants were identified, and the most common was c.760C > T, with an allelic frequency of 32% (16/50), followed by c.1400C > G (7/50, 14%), and c.51C > G (7/50, 14%).
Data from this study revealed that 24% (6/25) of PCD cases would have been missed by conventional NBS. This high-throughput iPLEX assay is a powerful tool for PCD genotyping. The addition of this second-tier genetic screening to the current NBS program could identify missed PCD cases, thereby increasing PCD detection. However, further studies are needed to optimise the workflow of the new screening algorithm and to evaluate the cost-effectiveness of this screening approach.
全世界普遍开展了针对原发性肉碱缺乏症（PCD）的新生儿筛查（NBS），但其敏感度较差。本研究旨在评估通过纳入二级基因检测来改善筛查的可行性。
我们开发了一种 Agena iPLEX 检测方法，用于鉴定中国人群中 17 种常见的 SLC22A5 突变，并将其作为二级筛查应用于 NBS。2017 年 1 月至 2018 年 12 月，我们使用串联质谱法对 204777 名新生儿进行了 PCD 的 NBS。共有 316 例（0.15%）残余 NBS 阳性标本游离肉碱（C0）水平较低，进行了二级筛查。该筛查在 20 名携带 SLC22A5 基因双等位基因突变的筛查阳性新生儿、99 名携带 1 种突变的携带者和 197 名筛查阴性无突变的新生儿中发现了 20 例筛查阳性新生儿。在 99 名携带者中，进一步的遗传分析发现有 4 名新生儿携带第二种致病 SLC22A5 基因突变。在 197 名筛查阴性者中，有 4 名新生儿的 C0 水平持续较低，进一步的遗传分析显示有 1 名新生儿携带两种新的 SLC22A5 致病性变异。共 25 名新生儿被诊断为 PCD，阳性预测值为 7.91%（25/316）。根据这些数据，我们估计泉州 PCD 的发病率估计为 1:8191。鉴定出 13 种不同的 SLC22A5 变异，最常见的是 c.760C>T，等位基因频率为 32%（16/50），其次是 c.1400C>G（7/50，14%）和 c.51C>G（7/50，14%）。
本研究的数据显示，24%（6/25）的 PCD 病例将被常规 NBS 漏诊。这种高通量 iPLEX 检测是一种用于 PCD 基因分型的强大工具。将这种二级基因筛查添加到当前的 NBS 项目中，可以发现漏诊的 PCD 病例，从而提高 PCD 的检出率。然而，还需要进一步的研究来优化新筛查算法的工作流程，并评估这种筛查方法的成本效益。
