Pregnancy outcomes and short-term follow-up of fetuses with recurrent microdeletion-microduplication syndromes featuring variable penetrance in prenatal diagnosis

Abstract

Objective: To retrospectively determine the incidence of recurrent microdeletion/microduplication syndromes in a prenatal cohort from Ningbo, China, and to evaluate pregnancy outcomes and live births in women carrying recurrent copy number variations (CNVs), this study aims to provide more clinical insights for assessing the variable penetrance of recurrent CNVs.

Method: A retrospective analysis was conducted on 7,645 pregnant women who underwent testing between 2019 and 2022 to investigate the incidence of locally recurrent microdeletion/microduplication syndromes and associated pregnancy outcomes. Chromosomal microarray analysis (CMA) identified 162 cases of recurrent CNVs. These cases were followed up to assess pregnancy outcomes, focusing on the implications of variable penetrance. The 162 patients were divided into two groups: Group 1 (n = 34), pregnancies with suspected genetic disease; Group 2 (n = 128), pregnancies with no apparent fetal abnormalities detected by ultrasonography. The study compared CNV pathogenicity and the rate of abnormal live births between the two groups.

Results: Among the 7,645 microarray tests, 162 cases of recurrent CNVs were identified across 34 distinct recurrent regions, yielding an incidence rate of 2.1%. The highest proportion was observed in pregnancies of advanced maternal age (45/162, 28%), followed by cases with high-risk serological screening results (40/162, 25%) and abnormal non-invasive prenatal testing (NIPT) results (38/162, 23%). CMA revealed that the most frequently involved chromosomes were chromosome 16, chromosome 22, and the sex chromosomes (X and Y): 3 recurrent regions on chromosome 16 affected 37 fetuses; 2 recurrent regions on chromosome 22 affected 28 fetuses; and 4 recurrent regions on sex chromosomes (X and Y) affected 47 fetuses. Follow-up analysis showed a pregnancy termination rate of 36.97% among the 162 cases. In Group 1, 37% (13/34) of women continued their pregnancies, and 3 of the live births exhibited postnatal congenital cardiac anomalies; the remaining had no reported anomalies. In Group 2, 41% (54/128) continued the pregnancy, with postnatal anomalies identified in 11 cases. A chi-square (χ²) test showed no statistically significant difference in the proportion of abnormal live births between the two groups (P > 0.001).

Conclusion: CMA enabled detection and analysis of recurrent CNVs in prenatal samples, offering insight into their clinical manifestations and associated pregnancy outcomes, particularly in cases with variable penetrance. Our findings enhance understanding of the clinical phenotypes of recurrent CNVs and provide additional data support for genetic counseling. Importantly, we found that fetuses carrying CNVs, despite the absence of structural anomalies, may face risks comparable to those with visible malformations. Therefore, we strongly recommend invasive prenatal diagnostic procedures when NIPT or serologic screening indicates abnormalities, as CMA-detected pathogenic CNVs can significantly impact prognosis and clinical decision making.

Keywords

Chromosomal microarray analysis (CMA) / prenatal diagnosis / clinical phenotype / recurrent region

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