Li Huanyun, Li Shaojun, Zhao Zhenhua, Kong Lingrong, Fu Xinyu, Zhu Jingqi, Feng Jun, Tang Weiqin, Wu Di, Kong Xiangdong
Genetic and Prenatal Diagnosis Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Celula (China) Medical Technology Co., Ltd., Chengdu, China.
Orphanet J Rare Dis. 2025 Jan 27;20(1):40. doi: 10.1186/s13023-025-03558-x.
Noninvasive prenatal diagnosis (NIPD) has been proven feasible for non-syndromic hearing loss (NSHL) in singleton pregnancies. However, previous research is limited to the second trimester and the application in twin pregnancies is blank. Here we provide a novel algorithmic approach to assess singleton and twin pregnancies in the first trimester.
A 324.614 kb capture panel was designed to selectively enrich target regions. Parental haplotypes were constructed by target sequencing of blood samples from the parents and the proband. Then single nucleotide polymorphisms (SNP) within target regions were classified into four and six categories in singleton and twin pregnancy, respectively. Combining relative haplotype dosage change (RHDO) and the Bayes factor (BF), fetal fraction (FF) and fetal genotype were deduced in singleton and twin pregnancies. The pregnant women's NIPD results were validated by invasive prenatal diagnosis and Sanger sequencing.
Sixteen women with singleton pregnancies and one woman with a twin pregnancy were recruited. Among the 16 singleton pregnancies, NIPD was successfully applied in 15 families and the coincidence rate with invasive prenatal diagnosis was 100% (15/15). Only one family NIPD result is "no call" because the imbalance distribution of SNP sites makes it difficult to estimate recombination events. Most (13/15) of pregnant women were diagnosed in the first trimester and the earliest gestation week was the 7th week. The twin pregnancy was a dichorionic diamniotic twin (DCDA). NIPD confirmed one fetus is affected, and another is a carrier with c.299_300delAT of GJB2 gene.
This study represents the pioneering evidence in the field, demonstrating the feasibility of NIPD for NSHL in twin pregnancies. Moreover, it provides a novel and advanced diagnostic approach for families at high risk of NSHL during pregnancy, offering earlier detection, enhanced safety, and improved accuracy.
无创产前诊断（NIPD）已被证明对单胎妊娠中的非综合征性听力损失（NSHL）可行。然而，先前的研究仅限于孕中期，且在双胎妊娠中的应用尚属空白。在此，我们提供一种新颖的算法方法来评估孕早期的单胎和双胎妊娠。
设计一个324.614 kb的捕获面板以选择性富集目标区域。通过对父母及先证者的血样进行目标测序构建亲本单倍型。然后将目标区域内的单核苷酸多态性（SNP）在单胎和双胎妊娠中分别分为四类和六类。结合相对单倍型剂量变化（RHDO）和贝叶斯因子（BF），推断单胎和双胎妊娠中的胎儿游离DNA比例（FF）和胎儿基因型。孕妇的NIPD结果通过侵入性产前诊断和桑格测序进行验证。
招募了16名单胎妊娠妇女和1名双胎妊娠妇女。在16名单胎妊娠中，NIPD成功应用于15个家庭，与侵入性产前诊断的符合率为100%（15/15）。只有一个家庭的NIPD结果为“无法判断”，因为SNP位点的不平衡分布使得难以估计重组事件。大多数（13/15）孕妇在孕早期被诊断，最早孕周为第7周。该双胎妊娠为双绒毛膜双羊膜囊双胎（DCDA）。NIPD证实一个胎儿患病，另一个是GJB2基因c.299_300delAT的携带者。
本研究代表了该领域的开创性证据，证明了NIPD用于双胎妊娠中NSHL的可行性。此外，它为孕期NSHL高风险家庭提供了一种新颖且先进的诊断方法，实现了更早检测、更高安全性和更高准确性。
