Prenatal phenotypes and pregnancy outcomes of fetuses with 16p11.2 microdeletion/microduplication. Prenatal phenotypes and pregnancy outcomes of fetuses with 16p11.2 microdeletion/microduplication

Background: Chromosomal 16p11.2 deletions and duplications are genomic disorders which are characterized by neurobehavioral abnormalities, obesity, congenital abnormalities and so on. However, the prenatal phenotypes of 16p11.2 copy number variations (CNVs) are still not well described till now. This study aimed to provide an elaborate summary of intrauterine phenotypic features for such genomic disorders. Methods: Twenty prenatal amniotic fluid samples diagnosed with 16p11.2 microdeletions/microduplications were obtained from pregnant women who opted for invasive prenatal testing. Karyotypic analysis and chromosomal microarray analysis (CMA) were performed in parallel. The pregnancy outcomes and health conditions after birth for all cases were followed up. Meanwhile, we made a pooled analysis on the prenatal phenotypes for the published cases carrying 16p11.2 CNVs. Results: 20 fetuses (20/20884, 0.10%) with 16p11.2 CNVs were identified: five 16p11.2 BP2-BP3 deletion, ten 16p11.2 BP4-BP5 deletion and five 16p11.2 BP4-BP5 duplication. Abnormal ultrasound findings were recorded in ten participants with 16p11.2 deletions.Various degrees of intrauterine phenotypic features, ranging from normal to abnormal, were observed. No ultrasound abnormalities were observed for all 16p11.2 duplication cases during the pregnancy period. For 16p11.2 deletions, eleven cases terminated their pregnancies. For 16p11.2 duplications, four cases gave birth to healthy neonates except one was lost to follow up. Conclusions: Diverse prenatal phenotypes were presented in 16p11.2 CNVs, ranging from normal to abnormal. For 16p11.2 BP4-BP5 deletion, the most common structural and non-structural abnormalities were the abnormality of the vertebral column or rib and thickened nuchal translucency, respectively. 16p11.2 BP2-BP3 deletion might be closely associated with fetal growth restriction and single umbilical artery. No representative ultrasound findings for 16p11.2 duplication were observed till now. Considering the variable expressivity and incomplete penetrance of 16p11.2 CNVs, long term follow up after birth should be carried out for these cases. We identified 20 fetuses carrying the 16p11.2 microdeletions and microduplications using chromosomal microarray analysis. And diverse prenatal phenotypes and the critical genes involved in the deleted/duplicated regions were described in this study. Overall design: 15 pregnancies with 16p11.2 microdeletions and five with 16p11.2 microduplications were included. **Please note that raw data CEL files for ？samples (out of total ？) have been lost and thus are not provided***

背景：染色体16p11.2缺失与重复是一类以神经行为异常、肥胖、先天性畸形等为特征的基因组疾病。然而，截至目前，16p11.2拷贝数变异（copy number variations, CNVs）的产前表型仍未被充分阐明。本研究旨在详尽总结此类基因组疾病的宫内表型特征。
方法：本研究纳入20份经侵入性产前诊断确诊为16p11.2微缺失/微重复的产前羊水样本，样本来自自愿接受侵入性产前检查的孕妇。并行开展核型分析与染色体微阵列分析（chromosomal microarray analysis, CMA）。对所有研究对象的妊娠结局及产后健康状况进行随访。同时，对已发表的携带16p11.2 CNVs的病例的产前表型进行荟萃分析。
结果：本研究共检出20例携带16p11.2 CNVs的胎儿（占总检测数20884例的0.10%，20/20884），其中16p11.2 BP2-BP3微缺失5例、16p11.2 BP4-BP5微缺失10例、16p11.2 BP4-BP5微重复5例。10例16p11.2缺失病例存在超声异常表现。观察到程度各异的宫内表型特征，范围从正常到异常均有覆盖。所有16p11.2微重复病例的孕期超声均未发现异常。16p11.2缺失组中，11例选择终止妊娠；16p11.2重复组中，4例产下健康新生儿，其余1例失访。
结论：16p11.2 CNVs患者存在多样的产前表型，表型谱覆盖正常至异常范围。针对16p11.2 BP4-BP5微缺失，最常见的结构异常与非结构异常分别为脊柱或肋骨畸形及颈项透明层增厚。16p11.2 BP2-BP3微缺失可能与胎儿生长受限及单脐动脉密切相关。截至目前，尚未发现16p11.2微重复的特征性超声表现。鉴于16p11.2 CNVs存在表型异质性与不完全外显率，应对此类病例开展产后长期随访。本研究通过染色体微阵列分析检出20例携带16p11.2微缺失与微重复的胎儿，并阐明了该类病例多样的产前表型及缺失/重复区域内的关键基因。
总体研究设计：本研究纳入15例16p11.2微缺失妊娠病例与5例16p11.2微重复妊娠病例。**请注意：总样本中？份样本的原始CEL文件已丢失，故无法提供**