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

References

[1] SmajlagićD,BerlandS.Population prevalence and inheritance pattern of recurrent CNVs associated with neurodevelopmental disorders in 12,252 newborns and their parents.Eur J Hum Genet2021;29:205-15 PMCID:PMC7852900

[2] KendallKM,Escott-PriceV.Cognitive performance among carriers of pathogenic copy number variants: analysis of 152,000 UK biobank subjects.Biol Psychiatry2017;82:103-10

[3] MolloyCJ,McNicholasÁ,GallagherL.A review of the cognitive impact of neurodevelopmental and neuropsychiatric associated copy number variants.Transl Psychiatry2023;13:116 PMCID:PMC10082763

[4] RichardsS,BaleS.Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Genet Med2015;17:405-24 PMCID:PMC4544753

[5] MeffordHC,BakerC.Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes.N Engl J Med2008;359:1685-99

[6] HuangJ,GaoY.Application of genomic copy number variation detection technology in prenatal diagnosis of 7617 pregnant women with serological screening abnormalities during the second trimester of pregnancy.Zhonghua Yi Xue Yi Chuan Xue Za Zhi2022;39:468-73

[7] CoeBP,RosenfeldJA.Refining analyses of copy number variation identifies specific genes associated with developmental delay.Nat Genet2014;46:1063-71 PMCID:PMC4177294

[8] TropeanoM,DobsonRJ.Male-biased autosomal effect of 16p13.11 copy number variation in neurodevelopmental disorders.PLoS One2013;8:e61365 PMCID:PMC3630198

[9] BlasegNA,PatelRA,PohlJF.Gastrointestinal pathologies in pediatric patients with cystic fibrosis undergoing endoscopy: a single-center retrospective review over 15 years.Cureus2024;16:e59018 PMCID:PMC11127755

[10] WangD,YangX.Microduplication of 16p11.2 locus potentiates hypertrophic obesity in association with imbalanced triglyceride metabolism in white adipose tissue.Mol Nutr Food Res2022;66:e2100241 PMCID:PMC9286681

[11] RosenfeldJA,BejjaniBA.Speech delays and behavioral problems are the predominant features in individuals with developmental delays and 16p11.2 microdeletions and microduplications.J Neurodev Disord2010;2:26-38 PMCID:PMC3125720

[12] LiL,LinS,FangQ.Discordant phenotypes in monozygotic twins with 16p11.2 microdeletions including the SH2B1 gene.Am J Med Genet A2017;173:2284-8

[13] MasunoM,TanakaY.De novo trisomy 16p11.2-qter: report of an infant.Am J Med Genet2000;92:308-10

[14] SuJ,FuH.Association of prenatal renal ultrasound abnormalities with pathogenic copy number variants in a large Chinese cohort.Ultrasound Obstet Gynecol2022;59:226-33

[15] JensenM,PizzoL.Combinatorial patterns of gene expression changes contribute to variable expressivity of the developmental delay-associated 16p12.1 deletion.Genome Med2021;13:163 PMCID:PMC8522054

[16] Spineli-SilvaS,Gil-da-Silva-LopesVL.Distal deletion at 22q11.2 as differential diagnosis in Craniofacial Microsomia: Case report and literature review.Eur J Med Genet2018;61:262-8

[17] VyasS,BaldridgeD.22q11.2 duplication: a review of neuropsychiatric correlates and a newly observed case of prototypic sociopathy.Cold Spring Harb Mol Case Stud2019;5:a004291 PMCID:PMC6913156

[18] CaiM,SuL.Prenatal diagnosis of 22q11.2 copy number abnormalities in fetuses via single nucleotide polymorphism array.Mol Biol Rep2020;47:7529-35 PMCID:PMC7588391

[19] RosenfeldJA,EichlerEE,ShafferLG.Estimates of penetrance for recurrent pathogenic copy-number variations.Genet Med2013;15:478-81

[20] AlstonCL,DibleyMG.Bi-allelic mutations in NDUFA6 establish its role in early-onset isolated mitochondrial complex i deficiency.Am J Hum Genet2018;103:592-601 PMCID:PMC6174280

[21] FerreiraCR.Lysosomal storage diseases.Transl Sci Rare Dis2017;2:1-71 PMCID:PMC5685203

[22] TahataS,LanpherB.Complex phenotypes in ALG12-congenital disorder of glycosylation (ALG12-CDG): case series and review of the literature.Mol Genet Metab2019;128:409-14

[23] LelieveldSH,PfundtR.Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability.Nat Neurosci2016;19:1194-6

[24] TortiE,PalmerEE.Variants in TCF20 in neurodevelopmental disability: description of 27 new patients and review of literature.Genet Med2019;21:2036-42 PMCID:PMC7171701

[25] Developmental Disorders Study. Prevalence and architecture of de novo mutations in developmental disorders.Nature2017;542:433-8 PMCID:PMC6016744

[26] BraultJ,VanceGH.Klinefelter's syndrome with maternal uniparental Disomy X, interstitial Xp22.31 deletion, X-linked Ichthyosis, and severe central nervous system regression.J Pediatr Genet2021;10:222-9 PMCID:PMC8416204

[27] GubbSJA,UnderwoodJFG.Medical and neurobehavioural phenotypes in male and female carriers of Xp22.31 duplications in the UK Biobank.Hum Mol Genet2020;29:2872-81 PMCID:PMC7566349

[28] WentLN,SangerR,GavinJ.X-linked ichthyosis: linkage relationship with the Xg blood groups and other studies in a large Dutch kindred.Ann Hum Genet1969;32:333-45

[29] CraneJS.X-linked ichthyosis. Treasure Island: StatPearls, 2025.

[30] ZhuY,CaoD,JiangM.Chromosomal microarray analysis of infertile men with azoospermia factor microdeletions.Gene2020;735:144389

[31] VogtPH,DeibelB,ZimmerJ.Human AZFb deletions cause distinct testicular pathologies depending on their extensions in Yq11 and the Y haplogroup: new cases and review of literature.Cell Biosci2021;11:60 PMCID:PMC7995748

[32] LiuC,MuC.The association of partial azoospermia factor C deletions and male infertility in Northwestern China.Hum Hered2019;84:144-50

[33] FerlinA,RossiA,ForestaC.The human Y chromosome's azoospermia factor b (AZFb) region: sequence, structure, and deletion analysis in infertile men.J Med Genet2003;40:18-24 PMCID:PMC1735253

[34] NassisiM,ArettiA.Ocular features in Williams-Beuren syndrome: a review of the literature.Curr Opin Ophthalmol2023;34:514-21

[35] ThomRP.Psychiatric and behavioral manifestations of Williams syndrome.Curr Opin Psychiatry2024;37:65-70

[36] KozelBA,KimCA.Williams syndrome.Nat Rev Dis Primers2021;7:42 PMCID:PMC9437774

[37] JiX,WangY.Prenatal diagnosis of recurrent distal 1q21.1 duplication in three fetuses with ultrasound anomalies.Front Genet2018;9:275 PMCID:PMC6109635

[38] UpadhyaiP,GuleriaVS,GirishaKM.Recurrent 1q21.1 deletion syndrome: report on variable expression, nonpenetrance and review of literature.Clin Dysmorphol2020;29:127-31 PMCID:PMC8555865

[39] PangH,KimYM.Disorders associated with diverse, recurrent deletions and duplications at 1q21.1.Front Genet2020;11:577 PMCID:PMC7325322