摘要目的:探讨早孕期胎儿鼻骨发育异常的遗传学病因。方法:回顾性分析2015年1月至2023年5月422例孕11～13周 +6超声筛查提示胎儿鼻骨发育异常，早孕期于广西壮族自治区妇幼保健院产前诊断与优生遗传科接受绒毛活检产前诊断的单胎妊娠病例的临床资料。所有病例均行染色体核型分析及单核苷酸多态性微阵列芯片（single nucleotide polymorphism array，SNP-array）分析。根据是否合并其他异常超声指标分为非孤立性（247例）和孤立性组（175例）。分析2组的介入性产前诊断结果、染色体异常分布情况、拷贝数变异（copy number variation，CNV）检出情况，以及孕妇年龄、异常超声指标数目与染色体异常的关系和妊娠结局。采用 χ2检验（连续校正 χ2检验或Fisher精确概率法）进行统计学分析。 结果:（1）422例中，262例（62.1%）经2种技术检测均未见异常；160例检出异常，其中145例（34.4%）2种技术检测结果均异常且异常类型一致；2例（0.5%）核型分析检出染色体相互易位而SNP-array分析未检出；13例（3.1%）染色体核型分析未见异常，而SNP-array分析结果异常。本研究染色体异常的总体检出率为37.9%（160/422），与染色体核型分析相比，SNP-array分析额外检出率为4.7%（13/275）。（2）160例染色体异常包括140例非整倍体、18例CNV及2例染色体相互易位。非孤立组染色体异常总体检出率、非整倍体及致病性CNV检出率均高于孤立组［74.3%（130/175）与12.1%（30/247）， χ2=168.02；68.0%（119/175）与8.5%（21/247）， χ2=163.56；5.7%（10/175）与0.8%（2/247）， χ2=4.74； P值均<0.05］。SNP-array分析共检出18例CNV，其中孤立组8例，非孤立组10例。（3）422例孕妇年龄为（33.1±5.4）岁。孤立和非孤立组中，高龄孕妇（预产期年龄≥35岁）染色体异常检出率均高于非高龄者［孤立组：20.0%（17/85）与8.6%（14/162）， χ2=6.55；非孤立组：82.1%（69/84）与65.9%（60/91）， χ2=5.92； P值均=0.010］；不论孕妇是否高龄，非孤立组的染色体异常检出率均高于孤立组（ χ2值分别为65.28和92.42， P值均<0.001）。（4）非孤立组中，鼻骨发育异常合并1项和>1项异常超声指标时的染色体异常检出率分别为69.0%（78/113）和83.9%（52/62）。合并颈项透明层增厚时，胎儿染色体异常检出率为73.2%（71/97），高于合并其他单个指标异常时的染色体异常检出率（7/16）（ χ2=5.57， P=0.020）。（5）核型分析及SNP-array分析结果均未检出异常的262例中，活产241例（92.0%），分娩孕周39周（32~41周）引产12例（4.6%），流产5例（1.9%），失访4例（1.5%）。孤立组活产率高于非孤立组［86.9%（213/245）与20.2%（35/173）， χ2=187.00， P<0.001］。 结论:早孕期鼻骨发育异常胎儿有较高的染色体异常率和CNV检出率。对于早孕期胎儿鼻骨发育异常的病例，无论孤立性或非孤立性，均建议行介入性产前诊断。合并其他异常指标时，胎儿的遗传学病因更为复杂，应向患者提供详细的遗传咨询。

abstractsObjective:To investigate the genetic causes of fetuses with abnormal nasal bone development in early pregnancy.Methods:A retrospective study was conducted which involved 422 cases of singleton pregnancies with nasal bone development abnormalities indicated by ultrasound screening at 11 to 13 weeks and 6 days of gestation, who underwent chorionic villus sampling for prenatal diagnosis at the Prenatal Diagnosis and Genetic Center, Maternity & Child Health Hospital of Guangxi Zhuang Autonomous Region from January 2015 to May 2023. All cases underwent chromosomal karyotype analysis and single nucleotide polymorphism array (SNP-array) analysis. Based on whether other abnormal ultrasound indicators were present, the cases were divided into isolated (175 cases) and non-isolated groups (247 cases). The results of invasive prenatal diagnosis, distribution of chromosomal abnormalities, detection of copy number variation (CNV) in fetuses with nasal bone development abnormalities, the relationship between maternal age, number of abnormal ultrasound indicators and chromosomal abnormalities, and pregnancy outcomes were analyzed. Statistical analysis was performed using the Chi-square test (continuity correction Chi-square test or Fisher's exact test). Results:(1) Among the 422 cases, 262 cases (62.1%) showed no abnormalities with both detection techniques; 160 cases had abnormalities, including 145 cases (34.4%) had consistent abnormal results and types of abnormalies with the two techniques; two cases (0.5%) had chromosomal translocations detected by karyotype analysis but not by SNP-array analysis; 13 cases (3.1%) had no abnormalities detected by karyotype analysis but had abnormal SNP-array results. This study's overall detection rate of chromosomal abnormalities was 37.9% (160/422), with an additional detection rate of 4.7% (13/275) using SNP-array technology. (2) Among the 160 cases of chromosomal abnormalities, there were 140 cases of aneuploidy, 18 cases of CNV, and two cases of chromosomal translocation. The overall detection rate of chromosomal abnormalities and the detection of aneuploidy, and pathogenic CNV in the non-isolated group was higher than that in the isolated group [74.3% (130/175) vs. 12.1% (30/247), χ2=168.02; 68.0% (119/175) vs. 8.5% (21/247), χ2=163.56; 5.7% (10/175) vs. 0.8% (2/247), χ2=4.74; all P<0.05]. Eighteen cases of CNV were detected using SNP-array technology, including eight cases in the isolated group and ten cases in the non-isolated group. (3) The age of the 422 pregnant women was (33.1±5.4) years. In both isolated and non-isolated groups, the detection rate of chromosomal abnormalities was higher in women of advanced age (expected delivery age ≥35 years) than those not [isolated group: 20.0% (17/85) vs. 8.6% (14/162), χ2=6.55; non-isolated group: 82.1% (69/84) vs. 65.9% (60/91), χ2=5.92; both P=0.010]; regardless of maternal age, the detection rate of chromosomal abnormalities in the non-isolated group was significantly higher than that in the isolated group ( χ2 were 65.28 and 92.42, respectively, both P<0.001). (4) In the non-isolated group, the detection rates of chromosomal abnormalities were 69.0% (78/113) and 83.9% (52/62) when nasal bone abnormalities were combined with one or more other abnormal ultrasound indicators, respectively. When combined with increased nuchal translucency, the detection rate of fetal chromosomal abnormalities was 73.2% (71/97), higher than the detection rate when combined with other single indicators (7/16) ( χ2=5.57, P=0.020). (5) Among the 262 cases with negative karyotype analysis and SNP-array results, 241 cases (92.0%) resulted in live births, with a gestational age at delivery of 39 weeks (32-41 weeks); 12 cases (4.6%) resulted in induced labor, five cases (1.9%) resulted in miscarriage, and four cases (1.5%) were lost to follow-up. The live birth rate in the isolated group was higher than that in the non-isolated group [86.9% (213/245) vs. 20.2% (35/173), χ2=187.00, P<0.001]. Conclusions:Fetuses with nasal bone developmental abnormalities in early pregnancy have a higher detection rate of chromosomal abnormalities and CNV. Invasive prenatal diagnosis is recommended for cases of nasal bone developmental abnormalities in early pregnancy, whether isolated or non-isolated. When combined with other abnormal indicators, the genetic etiology of the fetus is more complex, and detailed genetic counseling should be provided to the patient.