Incorporating Next-Generation Sequencing as a Second-Tier Test for Primary Carnitine Deficiency.

IF 1.5 4区医学 Q4 GENETICS & HEREDITY Molecular Genetics & Genomic Medicine Pub Date : 2024-09-01 DOI:10.1002/mgg3.70003

Yiming Lin, Zhenzhu Zheng, Weihua Lin, Weilin Peng

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Abstract

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.

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将新一代测序技术作为原发性肉碱缺乏症的二级检测方法。

背景：原发性肉碱缺乏症（PCD）的新生儿筛查（NBS）效果不佳。本研究旨在评估将新一代测序（NGS）作为 PCD 二级检测的可行性：方法：2020 年 3 月至 12 月间，对 60,070 名新生儿进行了遗传代谢紊乱筛查。选择游离肉碱（C0）水平低于 8.5 μmol/L 的新生儿进行二级基因检测：共有 130 名（0.22%）C0 水平较低的新生儿接受了二级基因检测，87 名（66.92%）基因检测结果呈阳性，30 名（23.08%）携带 SLC22A5 基因致病变体。6 名新生儿被确诊为 PCD。PCD的发病率约为1:10,012。结合二级 NGS 后，PPV 达到 20%。在 PCD 患者中发现的 8 个变异中，最常见的三个变异是 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）：我们的研究结果表明，结合二级 NGS 后，PPV 达到 20%。结论：我们的研究结果表明，与二级 NGS 结合使用后，PPV 达到 20%。基于 MS/MS 的 NBS 与二级 NGS 结合使用可有效降低假阳性率，检测出 PCD 患者。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Genetics & Genomic Medicine Biochemistry, Genetics and Molecular Biology-Genetics

CiteScore

4.20

自引率

0.00%

发文量

241

审稿时长

14 weeks

期刊介绍： Molecular Genetics & Genomic Medicine is a peer-reviewed journal for rapid dissemination of quality research related to the dynamically developing areas of human, molecular and medical genetics. The journal publishes original research articles covering findings in phenotypic, molecular, biological, and genomic aspects of genomic variation, inherited disorders and birth defects. The broad publishing spectrum of Molecular Genetics & Genomic Medicine includes rare and common disorders from diagnosis to treatment. Examples of appropriate articles include reports of novel disease genes, functional studies of genetic variants, in-depth genotype-phenotype studies, genomic analysis of inherited disorders, molecular diagnostic methods, medical bioinformatics, ethical, legal, and social implications (ELSI), and approaches to clinical diagnosis. Molecular Genetics & Genomic Medicine provides a scientific home for next generation sequencing studies of rare and common disorders, which will make research in this fascinating area easily and rapidly accessible to the scientific community. This will serve as the basis for translating next generation sequencing studies into individualized diagnostics and therapeutics, for day-to-day medical care. Molecular Genetics & Genomic Medicine publishes original research articles, reviews, and research methods papers, along with invited editorials and commentaries. Original research papers must report well-conducted research with conclusions supported by the data presented.