将下一代测序作为原发性肉碱缺乏症的二线检测方法。
Incorporating Next-Generation Sequencing as a Second-Tier Test for Primary Carnitine Deficiency.
机构信息
Department of Clinical Laboratory, Quanzhou Maternity and Children's Hospital, Quanzhou, Fujian, China.
Neonatal Disease Screening Center, Quanzhou Maternity and Children's Hospital, Quanzhou, Fujian, China.
出版信息
Mol Genet Genomic Med. 2024 Sep;12(9):e70003. doi: 10.1002/mgg3.70003.
BACKGROUND
Newborn screening (NBS) for primary carnitine deficiency (PCD) has poor performance. This study aimed to evaluate the feasibility of incorporating next-generation sequencing (NGS) as a second-tier PCD test.
METHODS
Between March and December 2020, 60,070 newborns were screened for inherited metabolic disorders. Newborns with free carnitine (C0) levels below 8.5 μmol/L were selected for second-tier genetic testing.
RESULTS
In total, 130 (0.22%) newborns with low C0 levels underwent second-tier genetic testing, 87 (66.92%) had positive genetic testing results, and 30 (23.08%) carried pathogenic variants of the SLC22A5 gene. Six newborns were diagnosed with PCD. The incidence of PCD was approximately 1 in 1:10,012 newborns. The PPV reached 20% after combining with second-tier NGS. Of the eight variants identified in patients with PCD, the three most common variants were c.760C>T (p.Arg254*), c.51C>G (p.Phe17Leu), and c.1400C>G (p.Ser467Cys). The C0 levels of patients with PCD were significantly lower than those of PCD carriers (p = 0.0026) and PCD-negative individuals (p = 0.0005).
CONCLUSIONS
Our results showed that the PPV reached 20% after combining with second-tier NGS. The MS/MS-based NBS and second-tier NGS combination can effectively reduce the false-positive rate and detect PCD in patients.
背景
新生儿筛查（NBS）在原发性肉碱缺乏症（PCD）中的应用效果不佳。本研究旨在评估将下一代测序（NGS）作为二线 PCD 检测方法的可行性。
方法
2020 年 3 月至 12 月，对 60070 例新生儿进行遗传性代谢疾病筛查。选择游离肉碱（C0）水平低于 8.5μmol/L 的新生儿进行二线基因检测。
结果
共有 130 例（0.22%）C0 水平低的新生儿接受二线基因检测，87 例（66.92%）检测结果阳性，30 例（23.08%）携带 SLC22A5 基因突变。6 例新生儿被诊断为 PCD。PCD 的发病率约为 1:10012。与二线 NGS 联合应用后，PPV 达到 20%。在 8 例 PCD 患者中发现的变异中，最常见的三种变异为 c.760C>T(p.Arg254*)、c.51C>G(p.Phe17Leu)和 c.1400C>G(p.Ser467Cys)。PCD 患者的 C0 水平明显低于 PCD 携带者（p=0.0026）和 PCD 阴性个体（p=0.0005）。
结论
我们的研究结果表明，与二线 NGS 联合应用后，PPV 达到 20%。基于 MS/MS 的 NBS 和二线 NGS 联合应用可以有效降低假阳性率，检测出患者的 PCD。
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