【摘要】 目的：临床上16p11.2微缺失胎儿出生后的表型主要包括孤独症、精神分裂症和智力障碍，并伴有肥胖和先天性畸形等表现，但有关16p11.2微缺失胎儿的产前表型研究有限，本研究旨在通过分析16p11.2微缺失胎儿的产前超声与遗传学特征的相关性，为临床遗传咨询提供参考。方法：收集2016年10月至2024年12月多中心产前诊断为16p11.2微缺失的60例胎儿临床资料，包括孕妇年龄、羊水穿刺的指征及孕周、胎儿超声检查及全基因组拷贝数变异测序(copy number variation sequencing,CNV-seq)检测结果，对胎儿父母同时进行CNV-seq检测，以明确变异来源，并对所有病例进行妊娠结局随访。结合产前超声表现、遗传学检测结果及妊娠结局，对16p11.2微缺失胎儿的产前超声表型及基因组变异特征进行系统分析。结果：在43 721例行CNV-seq检测的胎儿中共发现60例16p11.2微缺失(60/43 721,0.14%)，其中49例为近端缺失(BP4-BP5)、9例为远端缺失(BP2-BP3)、2例为大片段缺失(BP2-BP5)。49例16p11.2近端缺失(BP4-BP5)胎儿中18例存在结构异常(6例为半椎体并脊柱侧弯、4例为肾发育异常、2例为主动脉缩窄、6例为其他)、26例为超声软指标[11例为NT增厚(其中1例合并单脐动脉)、6例为轻度脑室扩张(其中1例合并羊水过多)、9例为其他]和5例为超声检查无异常。9例16p11.2远端缺失(BP2-BP3)胎儿中2例存在宫内生长受限、4例为超声软指标(2例为鼻骨缺如、1例为单脐动脉、1例为NT增厚)及3例为超声检查无异常。2例16p11.2大片段缺失(BP2-BP5)胎儿中1例表现为膈疝，1例为NT增厚。72%的病例为新发变异(36/50),28%遗传自父母(14/50),67%的病例选择终止妊娠(35/52)。结论：16p11.2微缺失胎儿的产前超声表型具有高度异质性，其中16p11.2近端缺失(BP4-BP5)产前主要表现为半椎体并脊柱侧弯、肾发育异常及NT增厚。而16p11.2远端缺失(BP2-BP3)则可能与宫内生长受限和超声软指标相关。更多还原

【Abstract】 Objective: The postnatal phenotypes of fetuses with 16p11.2 microdeletion mainly include autism spectrum disorder, schizophrenia, and intellectual disability, often accompanied by obesity and congenital malformations. However, studies on the prenatal phenotypes of fetuses with 16p11.2 microdeletion remain limited. This study aims to investigate the correlation between prenatal ultrasound findings and genetic characteristics of fetuses with 16p11.2 microdeletion, thereby providing evidence for clinical genetic counseling.Methods: Clinical data of 60 fetuses prenatally diagnosed with 16p11.2 microdeletion at multiple centers between October 2016 and December 2024 were collected. Data included maternal age, indications for amniocentesis and gestational age at testing, fetal ultrasound findings, and copy number variation sequencing(CNV-seq) results. CNV-seq was also performed in both parents to determine the origin of the variants. Pregnancy outcomes were followed up for all cases. Based on prenatal ultrasound findings, genetic test results, and pregnancy outcomes, the prenatal phenotypes and genomic characteristics of fetuses with 16p11.2 microdeletion were systematically analyzed. Results: Among 43 721 fetuses who underwent CNV-seq testing, 60 cases of 16p11.2 microdeletion were identified(60/43721, 0.14%). Of these, 49 cases had proximal deletions(BP4-BP5), 9 had distal deletions(BP2-BP3), and 2 had large deletions(BP2-BP5). Among the 49 fetuses with proximal 16p11.2 deletions(BP4-BP5), 18 had structural abnormalities, including 6 cases of hemivertebra with scoliosis, 4 cases of renal developmental abnormalities, 2 cases of coarctation of the aorta, and 6 cases of other abnormalities. Twenty-six fetuses presented with ultrasound soft markers, including 11 cases of increased nuchal translucency(NT) thickness(1 accompanied by a single umbilical artery), 6 cases of mild ventriculomegaly(1 accompanied by polyhydramnios), and 9 cases of other soft markers. Five fetuses showed no ultrasound abnormalities. Among the 9 fetuses with distal 16p11.2 deletions(BP2-BP3), 2 had intrauterine growth restriction, 4 presented with ultrasound soft markers(2 with absent nasal bone, 1 with a single umbilical artery, and 1 with increased NT thickness), and 3 had no ultrasound abnormalities. Among the 2 fetuses with large 16p11.2 deletions(BP2-BP5), 1 presented with congenital diaphragmatic hernia and the other with increased NT thickness. Of the 50 cases, 72%(36/50) were de novo variants and 28%(14/50) were inherited from a parent. Regarding pregnancy outcomes, 67%(35/52) of pregnancies were terminated.Conclusion: Prenatal ultrasound phenotypes of fetuses with 16p11.2 microdeletion are highly heterogeneous. Proximal 16p11.2 deletions(BP4-BP5) are primarily associated with hemivertebra accompanied by scoliosis, renal developmental abnormalities, and increased NT thickness. In contrast, distal 16p11.2 deletions(BP2-BP3) may be associated with intrauterine growth restriction and ultrasound soft markers.更多还原