Skeletal dysplasias (SDs) are common birth defects, but they are difficult to diagnose accurately according to only the limited phenotypic information available from ultrasound during the pregnancy. To evaluate the application of whole-exome sequencing (WES) and expand the data in the prenatal molecular diagnosis of fetuses with SDs, we collected 55 fetuses with SDs based on ultrasonographic features. WES of the fetuses or parent-fetus trio were subjected to sequential tests and produced a diagnostic yield of 64% (35/55). 65% (11/17) of families with a history of adverse pregnancies were diagnosed, 16 genes were involved and 37 different pathogenic or likely pathogenic variants were identified, including 14 novel variants, which were first reported in this study. De novo variants were identified in 21 cases (60%, 21/35) among the fetuses with a genetic diagnosis. The pathogenicity of two novel splice-site variants was confirmed by constructing minigene in vitro. Our results revealed that WES can provide new evidence for the relationship between the genotype and phenotype of fetuses with SDs, as well as broaden the mutation spectrum of detected genes, which is significant for prenatal diagnosis and genetic counseling.

中文翻译：

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55例骨骼发育不良胎儿全外显子测序的分子诊断：一项回顾性队列研究

骨骼发育不良 (SDs) 是常见的出生缺陷，但仅根据怀孕期间超声提供的有限表型信息很难准确诊断。为了评估全外显子组测序 (WES) 的应用并扩展 SD 胎儿产前分子诊断中的数据，我们根据超声特征收集了 55 名 SD 胎儿。胎儿或父母-胎儿三人组的 WES 进行顺序测试并产生 64% (35/55) 的诊断率。65% (11/17) 的有不良妊娠史的家族被诊断出来，涉及 16 个基因，并鉴定出 37 个不同的致病或可能致病变异，其中包括 14 个新变异，这些变异是本研究中首次报道的。在 21 例（60%，21/35) 在基因诊断的胎儿中。通过体外构建小基因证实了两种新剪接位点变异的致病性。我们的研究结果表明，WES可以为SDs胎儿基因型和表型之间的关系提供新的证据，并拓宽检测基因的突变谱，对产前诊断和遗传咨询具有重要意义。