The application of next-generation sequencing to fetal pathology has proved to increase the diagnostic yield in fetuses with abnormal ultrasounds. We retrospectively reviewed genetic data of 30 selected cases studied through targeted resequencing of OMIM genes. In our experience, clinical data proved to be essential to support diagnostic reasoning and enhance variants’ assessment. The molecular diagnosis was reached in 19/30 (63%) cases. Only in 7/19 cases the molecular diagnosis confirmed the initial diagnostic hypothesis, showing the relevance of the genotype-first approach. According to the genotype-phenotype correlation, we were able to divide the solved cases into three groups: i) the correlation is well established but it was missed due to lack of specificity, unusual presentation or recent description; ii) the clinical presentation is much more severe than currently known for the underlying condition; iii) the correlation does not recapitulate the entire phenotype, possibly due to the fetal presentation or multiple coexisting conditions. Moreover, we found a higher proportion of recessive diagnosis in abnormal fetuses compared to cohorts of individuals with developmental delay. Our findings suggest that fetal pathology may be enriched in rare alleles and/or in unusual combinations, counter-selected in postnatal genomes and thus contributing to both phenotypic extremeness and atypical presentation.

事实证明，将下一代测序技术应用于胎儿病理学可以提高超声异常胎儿的诊断率。我们回顾性研究了30例通过OMIM基因的靶向重测序研究的病例的遗传数据。根据我们的经验，事实证明，临床数据对于支持诊断推理和增强变体的评估至关重要。在19/30（63％）的情况下达到了分子诊断。仅在7/19例中，分子诊断证实了最初的诊断假设，显示了基因型优先方法的相关性。根据基因型与表型的相关性，我们能够将已解决的病例分为三类：i）相关性很好，但由于缺乏特异性，异常的表现或最近的描述而被遗漏了；ii）临床表现比潜在疾病严重得多。iii）相关性不能归纳完整的表型，可能是由于胎儿的表现或多种并存的情况。此外，与发育迟缓的人群相比，我们发现异常胎儿的隐性诊断比例更高。我们的发现表明，胎儿病理学可能富含罕见的等位基因和/或不寻常的组合，在出生后的基因组中反选，从而促进了表型的极端性和非典型的表现。与发育迟缓的人群相比，我们发现异常胎儿的隐性诊断比例更高。我们的发现表明，胎儿病理学可能富含罕见的等位基因和/或不寻常的组合，在出生后的基因组中反选，从而促进了表型的极端性和非典型的表现。与发育迟缓的人群相比，我们发现异常胎儿的隐性诊断比例更高。我们的发现表明，胎儿病理学可能富含罕见的等位基因和/或不寻常的组合，在出生后的基因组中反选，从而促进了表型的极端性和非典型的表现。