Influence of Validating the Parental Origin on the Clinical Interpretation of Fetal Copy Number Variations in 141 Core Family Cases

Overview

Journal Mol Genet Genomic Med

Specialty Genetics

Date 2019 Sep 3

PMID 31475483

Citations 7

Authors

Panlai Shi

Rui Li

Conghui Wang

Xiangdong Kong

Affiliations

Soon will be listed here.

Abstract

Background: The sources and variants types of the copy number variations (CNVs) in prenatal fetal, and the critical role of parental origin on the interpretation of fetal CNVs are unclear.

Methods: One hundred and forty-one prenatal core families with abnormal CNVs were selected and performed by low-coverage massively parallel CNV sequencing (CNV-seq).

Results: The data showed that 72.3% of fetal CNVs were derived from parents, and 27.7% were new variations. Sixty-three cases were heterozygous deletion, 70 cases were threefold duplication, six cases were complex deletion and duplication, and two cases were fourfold repeats. That means the rate of heterozygous deletion and duplication was approximate one. In addition, in parental-derived fetal abnormal CNVs reports, before validating parental origin, 62 CNVs were variants of uncertain significance (VUS), 15 CNVs were likely benign, 20 CNVs were likely pathogenic, and 5 CNVs were pathogenic. However, after validating parental origin, the total clinical significance changed into 12 VUS, 89 likely benign, 1 likely pathogenic, and 0 pathogenic. The clinical interpretation of 78.4% fetal CNVs was changed and tended to be benign after parental CNVs were detected. Besides, we followed up all families. 93.3% parental-derived fetal and 30.3% fetus in new mutation group were born healthy.

Conclusion: Parental origin verification has an important significance for interpretation on the clinical significance of fetal CNVs.

Citing Articles

Parent-of-origin testing of prenatal copy number variations: a retrospective study of 167 family cases.

Liu Y, Peng Y, Liang Z, Pan Q Sci Rep. 2025; 15(1):5979.

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Wang Y, Liu L, Fu F, Li R, Lei T, Huang R Genes (Basel). 2023; 14(10).

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Analysis of potential copy-number variations and genes associated with first-trimester missed abortion.

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Distribution and transmission of copy number variations of uncertain significance in 105 trios.

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Copy Number Variation Analysis of 5p Deletion Provides Accurate Prenatal Diagnosis and Reveals Candidate Pathogenic Genes.

Chu G, Li P, Wen J, Zheng G, Zhao Y, He R Front Med (Lausanne). 2022; 9:883565.

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References

Huang L, Jiang T, Liu C . Fetal loss after amniocentesis: analysis of a single center's 7,957 cases in China. Clin Exp Obstet Gynecol. 2015; 42(2):184-7. View

Bernhardt B, Kellom K, Barbarese A, Andrew Faucett W, Wapner R . An exploration of genetic counselors' needs and experiences with prenatal chromosomal microarray testing. J Genet Couns. 2014; 23(6):938-47. PMC: 4147030. DOI: 10.1007/s10897-014-9702-y. View

Zhang F, Gu W, Hurles M, Lupski J . Copy number variation in human health, disease, and evolution. Annu Rev Genomics Hum Genet. 2009; 10:451-81. PMC: 4472309. DOI: 10.1146/annurev.genom.9.081307.164217. View

Kiedrowski L, Owens K, Yashar B, Schuette J . Parents' Perspectives on Variants of Uncertain Significance from Chromosome Microarray Analysis. J Genet Couns. 2015; 25(1):101-11. DOI: 10.1007/s10897-015-9847-3. View

Valouev A, Ichikawa J, Tonthat T, Stuart J, Ranade S, Peckham H . A high-resolution, nucleosome position map of C. elegans reveals a lack of universal sequence-dictated positioning. Genome Res. 2008; 18(7):1051-63. PMC: 2493394. DOI: 10.1101/gr.076463.108. View

Liang D, Peng Y, Lv W, Deng L, Zhang Y, Li H . Copy number variation sequencing for comprehensive diagnosis of chromosome disease syndromes. J Mol Diagn. 2014; 16(5):519-526. DOI: 10.1016/j.jmoldx.2014.05.002. View

Miller D, Adam M, Aradhya S, Biesecker L, Brothman A, Carter N . Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010; 86(5):749-64. PMC: 2869000. DOI: 10.1016/j.ajhg.2010.04.006. View

Shi P, Li R, Wang C, Kong X . Influence of validating the parental origin on the clinical interpretation of fetal copy number variations in 141 core family cases. Mol Genet Genomic Med. 2019; 7(10):e00944. PMC: 6785431. DOI: 10.1002/mgg3.944. View

Abel H, Duncavage E . Detection of structural DNA variation from next generation sequencing data: a review of informatic approaches. Cancer Genet. 2014; 206(12):432-40. PMC: 4441822. DOI: 10.1016/j.cancergen.2013.11.002. View

10.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J . 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 Med. 2015; 17(5):405-24. PMC: 4544753. DOI: 10.1038/gim.2015.30. View

11.

Stosic M, Levy B, Wapner R . The Use of Chromosomal Microarray Analysis in Prenatal Diagnosis. Obstet Gynecol Clin North Am. 2018; 45(1):55-68. DOI: 10.1016/j.ogc.2017.10.002. View

12.

Margulies M, Egholm M, Altman W, Attiya S, Bader J, Bemben L . Genome sequencing in microfabricated high-density picolitre reactors. Nature. 2005; 437(7057):376-80. PMC: 1464427. DOI: 10.1038/nature03959. View

13.

Ku C, Teo S, Naidoo N, Sim X, Teo Y, Pawitan Y . Copy number polymorphisms in new HapMap III and Singapore populations. J Hum Genet. 2011; 56(8):552-60. DOI: 10.1038/jhg.2011.54. View

14.

Izetbegovic S, Mehmedbasic S . Early amniocentesis as a method of choice in diagnosing gynecological diseases. Acta Inform Med. 2014; 21(4):270-3. PMC: 3916177. DOI: 10.5455/aim.2013.21.270-273. View

15.

Alkan C, Coe B, Eichler E . Genome structural variation discovery and genotyping. Nat Rev Genet. 2011; 12(5):363-76. PMC: 4108431. DOI: 10.1038/nrg2958. View

16.

Wang J, Chen L, Zhou C, Wang L, Xie H, Xiao Y . Prospective chromosome analysis of 3429 amniocentesis samples in China using copy number variation sequencing. Am J Obstet Gynecol. 2018; 219(3):287.e1-287.e18. DOI: 10.1016/j.ajog.2018.05.030. View

17.

Wheeler E, Huang N, Bochukova E, Keogh J, Lindsay S, Garg S . Genome-wide SNP and CNV analysis identifies common and low-frequency variants associated with severe early-onset obesity. Nat Genet. 2013; 45(5):513-7. PMC: 4106235. DOI: 10.1038/ng.2607. View

18.

Zong C, Lu S, Chapman A, Xie X . Genome-wide detection of single-nucleotide and copy-number variations of a single human cell. Science. 2012; 338(6114):1622-6. PMC: 3600412. DOI: 10.1126/science.1229164. View

19.

Xie C, Tammi M . CNV-seq, a new method to detect copy number variation using high-throughput sequencing. BMC Bioinformatics. 2009; 10:80. PMC: 2667514. DOI: 10.1186/1471-2105-10-80. View

20.

Kearney H, Thorland E, Brown K, Quintero-Rivera F, South S . American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants. Genet Med. 2011; 13(7):680-5. DOI: 10.1097/GIM.0b013e3182217a3a. View