De novo copy number variants and parental age: Is there an association?

Wadhawan, Isha; Hai, Yang; Yousefi, Nastaran Foyouzi; Guo, Xiuqing; Graham, John M.; Rosenfeld, Jill A.

doi:10.1016/j.ejmg.2019.103829

Cited by 7 publications

(5 citation statements)

References 22 publications

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“…This large series from a laboratory from United States, included 127 prenatal cases, in which samples were collected according to clinical indications for prenatal diagnosis, reported non-significant differences between cases ( de novo CNVs) and controls (inherited CNVs). However, in the postnatal series, a maternal age effect was observed to be associated with a higher rate of de novo recurrent CNV [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

Have maternal or paternal ages any impact on the prenatal incidence of genomic copy number variants associated with fetal structural anomalies?

et al. 2021

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The objective of this study was to determine whether maternal or paternal ages have any impact on the prenatal incidence of genomic copy number variants (CNV) in fetuses with structural anomalies. We conducted a non-paired case-control study (1:2 ratio) among pregnancies undergoing chromosomal microarray analysis (CMA) because of fetal ultrasound anomalies, from December 2012 to May 2020. Pregnancies with any pathogenic copy number variant (CNV), either microdeletion or microduplication, were defined as cases. Controls were selected as the next two pregnancies with the same indication for CMA but with a normal result. Logistic regression was used, adjusting by use of assisted reproductive technology (ART) and parental smoking. Stratified analysis was performed according to CNV type (de novo/inherited and recurrent/non-recurrent). The study included 189 pregnancies: 63 cases and 126 controls. Mean maternal age in cases was 33.1 (SD 4.6) years and 33.9 (SD 6.0) years in controls. Mean paternal mean age was 34.5 (SD 4.8) years in cases and 35.8 (SD 5.8) years in controls. No significant differences in maternal or paternal age were observed, neither in stratified analysis according to the CNV type. Moreover, the proportion of cases were not significantly different between non-advanced and advanced ages, either considering paternal or maternal ages. The presence of pathogenic CNV at CMA in fetuses with structural anomalies was not found to be associated with advanced paternal or maternal age.

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Section: Discussionmentioning

confidence: 99%

Have maternal or paternal ages any impact on the prenatal incidence of genomic copy number variants associated with fetal structural anomalies?

et al. 2021

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“…Aging of the oocytes perse in pregnant women with AMA increases the risk of aneuploidy ( Aprigio et al, 2022 ). However, there is no evidence of the influence of increased paternal age on de novo CNV formation ( Wadhawan et al, 2020 ). We determined that AMA is a high-risk factor for autosomal aneuploidy and is also closely related to CNVs such as triploidy mosaicism, microduplication, microdeletion, and LOH.…”

Section: Discussionmentioning

confidence: 99%

“…However, the frequency of abnormal CNV in offspring was not related to maternal age, and the risk of abnormal CNV remained constant during the reproductive period of a women ( Sibbons et al, 2012 ). Most of the previous studies have suggested that CNVs are closely associated with maternal age; in particular, maternal age appears to increase the risk of the occurrence of de novo non-complex CNVs in progeny with intellectual disabilities or delayed developmental, however, there is no evidence that increasing paternal age has an effect on de novo CNV formation ( Ma et al, 2020 ; Wadhawan et al, 2020 ). Thus, factors involved in AMA must be identified for improved diagnosis and treatment of this condition.…”

Section: Introductionmentioning

confidence: 97%

Advanced maternal age: copy number variations and pregnancy outcomes

Cao

Dong

et al. 2023

Front. Genet.

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Objective: Adverse pregnancy outcomes are closely related to advanced maternal age (AMA; age at pregnancy ≥35 years). Little research has been reported on aneuploid abnormalities and pathogenic copy number variations (CNVs) affecting pregnancy outcomes in women with AMA. The purpose of this study was to assess CNVs associated with AMA in prenatal diagnosis to determine the characteristics of pathogenic CNVs and assist with genetic counseling of women with AMA.Methods: Among 277 fetuses of women with AMA, 218 (78.7%) were isolated AMA fetuses and 59 (21.3%) were non-isolated AMA fetuses and showed ultrasound anomalies from January 2021 to October 2022. Isolated AMA was defined as AMA cases without sonographic abnormalities. Non-isolated AMA was defined as AMA cases with sonographic abnormalities such as sonographic soft markers, widening of the lateral ventricles, or extracardiac structural anomalies. The amniotic fluid cells underwent routine karyotyping followed by single nucleotide polymorphism array (SNP-array) analysis.Results: Of the 277 AMA cases, karyotype analysis identified 20 chromosomal abnormalities. As well as 12 cases of chromosomal abnormalities corresponded to routine karyotyping, the SNP array identified an additional 14 cases of CNVs with normal karyotyping results. There were five pathogenetic CNVs, seven variations of uncertain clinical significance (VOUS), and two benign CNVs. The detection rate of abnormal CNVs in non-isolated AMA cases was increasing (13/59; 22%) than in isolated AMA cases (13/218; 5.96%) (p < 0.001). We also determined that pathogenic CNVs affected the rate of pregnancy termination in women with AMA.Conclusion: Aneuploid abnormalities and pathogenic CNVs affect pregnancy outcomes in women with AMA. SNP array had a higher detection rate of genetic variation than did karyotyping and is an important supplement to karyotype analysis, which enables better informed clinical consultation and clinical decision-making.

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“…Similarly, the mutation rate of de novo SNVs is known to increase markedly with paternal age 30 and more modestly with maternal age 37 . Moreover, the risk of aneuploidies is known to increase with maternal age 38 , but an association between parental age and increased de novo CNV has not been established 39 . We did not observe a significant association between de novo CNVs and parental age (Supplement S20).…”

Section: B Proportion Of De Novo Cnvs With Paternal Origin In Four St...mentioning

confidence: 99%

Detection and characterisation of copy number variants from exome sequencing in the DDD study

Danecek,

Gardner,

Fitzgerald

et al. 2023

Preprint

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Purpose Structural variants such as multi-exon deletions and duplications are an important cause of disease, but are often overlooked in standard exome/genome sequencing analysis. We aimed to evaluate the detection of copy number variants (CNVs) from exome sequencing (ES) in comparison to genome-wide low-resolution and exon-resolution chromosomal microarrays (CMA), and to characterise the properties of de novo CNVs in a large clinical cohort. Methods We performed CNV detection using ES of 13,462 parent-offspring trios in the Deciphering Developmental Disorders (DDD) study, and compared them to CNVs detected from exon-resolution array comparative genomic hybridization (aCGH) in 5,197 probands from the DDD study. Results Integrating calls from multiple ES-based CNV algorithms using random forest machine learning generated a higher quality dataset than using individual algorithms. Both ES- and aCGH-based approaches had the same sensitivity of 89% and detected the same number of unique pathogenic CNVs not called by the other approach. Of DDD probands pre-screened with low resolution CMA, 2.6% had a pathogenic CNV detected by higher resolution assays. De novo CNVs were strongly enriched in known DD-associated genes and exhibited no bias in parental age or sex. Conclusion ES-based CNV calling has higher sensitivity than low-resolution CMAs currently in clinical use, and comparable sensitivity to exon-resolution CMA. With sufficient investment in bioinformatic analysis, exome-based CNV detection could replace low-resolution CMA for detecting pathogenic CNVs.

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De novo copy number variants and parental age: Is there an association?

Cited by 7 publications

References 22 publications

Have maternal or paternal ages any impact on the prenatal incidence of genomic copy number variants associated with fetal structural anomalies?

Have maternal or paternal ages any impact on the prenatal incidence of genomic copy number variants associated with fetal structural anomalies?

Advanced maternal age: copy number variations and pregnancy outcomes

Detection and characterisation of copy number variants from exome sequencing in the DDD study

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