Lau Sydney A, Fawaz Romy I, Rigobello Robert, Bawazeer Shahad, Alajaji Nouf M, Faqeih Eissa, Li Yanchun, Feng Yanming, Xia Fan, Eng Christine M, Abedalthagafi Malak
Baylor Genetics, Houston, TX, United States.
Department of Medical Genetics, Children's Specialized Hospital, King Fahad Medical City, Riyadh, Saudi Arabia.
Front Med (Lausanne). 2024 Aug 5;11:1390693. doi: 10.3389/fmed.2024.1390693. eCollection 2024.
Cell-free fetal DNA (cffDNA) screening is a valuable tool in clinical practice for detecting chromosomal abnormalities and autosomal dominant (AD) conditions. This study introduces a novel proof-of-concept assay designed for autosomal recessive (AR) cffDNA screening, focusing on cases involving the NPC1 gene. We aim to illustrate the significant benefits of AR cffDNA screening in managing high-risk pregnancies, specifically where biallelic pathogenic variants in NPC1 cause Niemann-Pick disease, type C1 (NPC), a disorder marked by progressive neurodegeneration. Three participants for this study were recruited and gave consent to a hospital in Saudi Arabia. These participants were either carriers of NPC or had a first- or second-degree relative affected by the disorder. No specific criteria were set for the age of the participants. All were between 15 and 18 weeks of gestation. Using amplicon-based next-generation sequencing (NGS), we analyzed the zygosity and variants in cffDNA extracted from maternal peripheral blood. After amplicon NGS, analysis was completed by a custom data analysis pipeline that included in-house-built data processing scripts and commonly used software packages. Importantly, the results were not disclosed to the patients. Our findings showed that in all three cases, AR cffDNA screening results were consistent with standard invasive diagnostic testing. This screening method offers several advantages: it provides critical information to families earlier in the pregnancy compared to invasive diagnostic tests, and it helps to alleviate parental anxiety. Moreover, this non-invasive method can determine pregnancy status in the first trimester for known familial variants. Future research may extend this approach to screen for known disease-causing variants in common AR conditions.
游离胎儿DNA（cffDNA）筛查是临床实践中检测染色体异常和常染色体显性（AD）疾病的一项重要工具。本研究引入了一种全新的概念验证检测方法，用于常染色体隐性（AR）cffDNA筛查，重点关注涉及NPC1基因的病例。我们旨在阐明AR cffDNA筛查在管理高危妊娠中的显著益处，特别是在NPC1基因双等位基因致病性变异导致C1型尼曼-匹克病（NPC）的情况下，这是一种以进行性神经退行性变特征的疾病。本研究招募了三名参与者，并获得了沙特阿拉伯一家医院的同意。这些参与者要么是NPC的携带者，要么有一级或二级亲属受该疾病影响。对参与者的年龄未设定具体标准。所有参与者均处于妊娠15至18周之间。我们使用基于扩增子的下一代测序（NGS）技术，分析了从孕妇外周血中提取的cffDNA的纯合性和变异情况。扩增子NGS之后，通过一个定制的数据分析流程完成分析，该流程包括内部构建的数据处理脚本和常用的软件包。重要的是，结果未向患者披露。我们的研究结果表明，在所有三个病例中，AR cffDNA筛查结果与标准的侵入性诊断检测结果一致。这种筛查方法具有多个优点：与侵入性诊断检测相比，它能在妊娠早期为家庭提供关键信息，并有助于减轻父母的焦虑。此外，这种非侵入性方法能够在孕早期确定已知家族性变异的妊娠状态。未来的研究可能会扩展这种方法，以筛查常见AR疾病中已知的致病变异。
