Table1_Exome sequencing improves genetic diagnosis of congenital orofacial clefts.DOCX

Objective: This retrospective study aims to evaluate the utility of exome sequencing (ES) in identifying genetic causes of congenital orofacial clefts (OFCs) in fetuses with or without other structural abnormalities, and to further explore congenital OFCs genetic causes.
Methods: The study enrolled 107 singleton pregnancies diagnosed with fetal OFCs between January 2016 and May 2022, and categorized them into two groups: isolated cleft lip and/or palate (CL/CP) and syndromic CL/CP. Cases with positive karyotyping and chromosomal microarray analysis results were excluded. Whole-exome sequencing was performed on eligible fetuses and their parents. Monogenic variants identified by ES and perinatal outcomes were recorded and evaluated during postnatal follow-up.
Results: Clinically significant variants were identified in 11.2% (12/107) of fetuses, with no significant difference in detection rate between the isolated CL/CP group and the syndromic CL/CP group (8/83, 9.6% vs. 4/24, 16.7%, p = 0.553). Additionally, sixteen (16/107, 15.0%) fetuses had variants of uncertain significance. We identified 12 clinically significant variations that correlated with clinical phenotypes in 11 genes from 12 fetuses, with CHD7 being the most frequently implicated gene (n = 2). Furthermore, we observed a significant difference in termination rates and survival rates between the isolated CL/CP and syndromic CL/CP groups (41.0% vs. 70.8% and 56.6% vs. 20.8%, p < 0.05 for both).
Conclusion: Based on our findings, it is clear that ES provides a significant increase in diagnostic yield for the molecular diagnosis of congenital OFCs, thereby substantially improving the existing prenatal diagnostic capabilities. This study also sheds light on seven novel pathogenic variants, broadening our understanding of the genetic underpinnings of OFCs and expanding the disease spectrums of relevant genes.

研究目的：本回顾性研究旨在评估外显子组测序（exome sequencing, ES）在伴或不伴其他结构异常的胎儿先天性唇腭裂（congenital orofacial clefts, OFCs）的遗传病因识别中的应用价值，并进一步探索先天性唇腭裂的遗传致病机制。
研究方法：本研究纳入2016年1月至2022年5月期间确诊为胎儿唇腭裂的107例单胎妊娠病例，将其分为两组：孤立性唇裂伴/不伴腭裂（isolated cleft lip and/or palate, CL/CP）组与综合征性唇裂伴/不伴腭裂组。排除核型分析及染色体微阵列分析结果阳性的病例。对符合入组标准的胎儿及其父母实施全外显子组测序。记录并评估经外显子组测序检出的单基因变异及产后随访期间的围产期结局。
研究结果：本研究在11.2%（12/107）的胎儿中检测到临床意义明确的变异；孤立性CL/CP组与综合征性CL/CP组的检出率无显著统计学差异（8/83，9.6% vs. 4/24，16.7%，p=0.553）。此外，16例（16/107，15.0%）胎儿携带意义未明变异。本研究在12例胎儿的11个基因中识别出12个与临床表型相关的临床意义明确的变异，其中CHD7为最常受累的基因（n=2）。进一步分析显示，孤立性CL/CP组与综合征性CL/CP组的终止妊娠率及存活率均存在显著统计学差异（终止妊娠率：41.0% vs.70.8%；存活率：56.6% vs.20.8%，两组p值均<0.05）。
研究结论：基于本研究结果，外显子组测序可显著提升先天性唇腭裂的分子诊断检出率，从而有效改善现有产前诊断水平。本研究同时明确了7种全新致病变异，拓宽了我们对唇腭裂遗传致病基础的认知，并拓展了相关基因的疾病谱。