PDF(Pubmed)
Abstract：
Skeletal dysplasias are a group of diseases characterized by bone and joint abnormalities, which can be detected during prenatal ultrasound. Next-generation sequencing has rapidly revolutionized molecular diagnostic approaches in fetuses with structural anomalies. This review studies the additional diagnostic yield of prenatal exome sequencing in fetuses with prenatal sonographic features of skeletal dysplasias. This was a systematic review by searching PubMed for studies published between 2013 and July 2022 that identified the diagnostic yield of exome sequencing after normal karyotype or chromosomal microarray analysis (CMA) for cases with suspected fetal skeletal dysplasias based on prenatal ultrasound. We identified 10 out of 85 studies representing 226 fetuses. The pooled additional diagnostic yield was 69.0%. The majority of the molecular diagnoses involved de novo variants (72%), while 8.7% of cases were due to inherited variants. The incremental diagnostic yield of exome sequencing over CMA was 67.4% for isolated short long bones and 77.2% for non-isolated cases. Among phenotypic subgroup analyses, features with the highest additional diagnostic yield were an abnormal skull (83.3%) and a small chest (82.5%). Prenatal exome sequencing should be considered for cases with suspected fetal skeletal dysplasias with or without a negative karyotype or CMA results. Certain sonographic features, including an abnormal skull and small chest, may indicate a potentially higher diagnostic yield.
摘要：
骨骼发育不良是一组以骨骼和关节异常为特征的疾病，可以在产前超声检查中检测到。下一代测序迅速彻底改变了具有结构异常的胎儿的分子诊断方法。这篇综述研究了具有骨骼发育不良的产前超声特征的胎儿的产前外显子组测序的额外诊断率。这是一项系统评价，通过搜索PubMed在2013年至2022年7月之间发表的研究，这些研究确定了正常核型或染色体微阵列分析（CMA）后外显子组测序对基于产前超声的疑似胎儿骨骼发育不良病例的诊断率。我们确定了85项研究中的10项，代表226例胎儿。合并的额外诊断率为69.0%。大多数分子诊断涉及从头变异（72％），而8.7%的病例是由于遗传变异。外显子组测序相对于CMA的增加诊断率对于分离的短长骨是67.4%,对于非分离病例是77.2%。在表型亚组分析中，附加诊断率最高的特征是颅骨异常（83.3％）和小胸部（82.5％）。对于怀疑有或没有阴性核型或CMA结果的胎儿骨骼发育不良的病例，应考虑产前外显子组测序。某些超声特征，包括异常的头骨和小胸部，可能表明潜在的更高的诊断产量。
