Variants of uncertain significance in prenatal microarrays: a retrospective cohort study

Mardy, Anne H.; Wiita, Arun P.; Wayman, Brette V.; Drexler, Kathryn; Sparks, Teresa N.; Norton, Mary E.

doi:10.1111/1471-0528.16427

Cited by 13 publications

(15 citation statements)

References 22 publications

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“…Our VUS prevalence of 7.0% was higher than some studies, 1,3,10–16,19,33,34 but comparable to 7.2% recorded in the Belgium national prenatal cohort 33 . The most common VUS in our study was the 15q11.2 deletion, which has a highly variable phenotype including neurodevelopmental delay, autism spectrum disorders, and obsessive‐compulsive disorders 35 .…”

Section: Discussionsupporting

confidence: 73%

Perinatal outcomes and genomic characteristics of fetal copy number variants: An individual record linkage study of 713 pregnancies

et al. 2023

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Objective: To determine the perinatal outcomes of fetuses diagnosed with a pathogenic copy number variant (CNV) or variant of uncertain significance (VUS); and to characterize these variants in terms of testing indication, genomic location, size, and inheritance. Methods:Retrospective study of singleton pregnancies with a pathogenic CNV or VUS from a single laboratory during 2012-2018. Probabilistic record linkage between the prenatal diagnosis dataset and perinatal outcome data for births from 20 weeks gestation was performed. If no birth record was found, this implied a pregnancy loss <20 weeks. Results:We included 6945 prenatal microarray results; a pathogenic CNV was detected in 230 (3.3%, 95% CI: 2.9%-3.8%) and a VUS in 483 (7.0%, 95% CI: 6.4%-7.6%). Of pregnancies with a pathogenic CNV, 20.0% (95% CI: 15.3%-25.6%) had a live birth, 3.0% (95% CI: 1.5%-6.2%) had a perinatal death (stillbirth or neonatal death), and 77% (95% CI: 71.1%-81.9%) had no birth record. Of those with a VUS, 64.4% (95% CI: 60.0%-68.5%) had a live birth, 1.8% (95% CI: 1.0%-3.5%) had a perinatal death, and no birth record was found for 33.7% (95% CI: 29.7%-38.1%).Most pathogenic CNVs (61.1%) were <7 Mb in size. The most common microdeletion syndromes were DiGeorge, Wolf-Hirschhorn, and Cri-du-chat syndromes. Conclusion:This study provides an overview of perinatal outcomes and frequency of recurrent CNVs observed in the prenatal microarray era. Key points What is already known about this topic?� Fetal copy number variants (CNVs) detected on chromosomal microarray have a wide range of clinical significance.� Large studies reporting perinatal outcome rates after a prenatal diagnosis of a CNV are rare.

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Section: Discussionsupporting

confidence: 73%

Perinatal outcomes and genomic characteristics of fetal copy number variants: An individual record linkage study of 713 pregnancies

et al. 2023

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“…A considerable number of patients with SPGF (n = 28; 13%) carried large deletions and duplications spanning over 1 Mb, whereas the respective carrier frequency in the normozoospermic fertile men was two times lower (n = 4, 6.5%). The proportion of large CNVs in infertile men is in a similar range as reported for patients with autism 43 or DD 44 . In comparison, a study of 7,877 Estonian Biobank participants identified only 2% of subjects as carriers of > 1 Mb CNVs 27 .…”

Section: Discussionsupporting

confidence: 72%

Microdeletions and microduplications linked to severe congenital disorders in infertile men

Kikas

Punab

Kasak

et al. 2023

Sci Rep

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Data on the clinical validity of DNA copy number variants (CNVs) in spermatogenic failure (SPGF) is limited. This study analyzed the genome-wide CNV profile in 215 men with idiopathic SPGF and 62 normozoospermic fertile men, recruited at the Andrology Clinic, Tartu University Hospital, Estonia. A two-fold higher representation of > 1 Mb CNVs was observed in men with SPGF (13%, n = 28) compared to controls (6.5%, n = 4). Seven patients with SPGF were identified as carriers of microdeletions (1q21.1; 2.4 Mb) or microduplications (3p26.3, 1.1 Mb; 7p22.3-p22.2, 1.56 Mb; 10q11.22, 1.42 Mb, three cases; Xp22.33; 2.3 Mb) linked to severe congenital conditions. Large autosomal CNV carriers had oligozoospermia, reduced or low-normal bitesticular volume (22–28 ml). The 7p22.3-p22.2 microduplication carrier presented mild intellectual disability, neuropsychiatric problems, and short stature. The Xp22.33 duplication at the PAR1/non-PAR boundary, previously linked to uterine agenesis, was detected in a patient with non-obstructive azoospermia. A novel recurrent intragenic deletion in testis-specific LRRC69 was significantly overrepresented in patients with SPGF compared to the general population (3.3% vs. 0.85%; χ2 test, OR = 3.9 [95% CI 1.8–8.4], P = 0.0001). Assessment of clinically valid CNVs in patients with SPGF will improve their management and counselling for general and reproductive health, including risk of miscarriage and congenital disorders in future offspring.

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“…This self‐selection of individuals with these traits pursuing this type of testing may initially falsely inflate the positive experiences of testing and receipt of results. Yet, at the same time, potential for uncertainty decreases (though is not eliminated) as the use of the new technology expands 26 …”

Section: Discussionmentioning

confidence: 99%

“…Yet, at the same time, potential for uncertainty decreases (though is not eliminated) as the use of the new technology expands. 26 Participants frequently did not fully differentiate the technical differences of pGS from the other types of clinical genetic testing other than the additional waiting time and being more comprehensive. We also encountered this in a prior study of pES.…”

Section: Discussionmentioning

confidence: 99%

Information is power: The experiences, attitudes and needs of individuals who chose to have prenatal genomic sequencing for fetal anomalies

et al. 2022

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Objective This study sought to evaluate the experiences of individuals who chose to participate in a study and receive prenatal genomic sequencing (pGS) for fetuses with congenital structural anomalies. Method Individuals who received research results of prenatal sequencing were invited to participate in semi‐structured interviews about their experiences. A constructivist grounded theory approach was used to code and analyze interviews. Results Thirty‐three participants from 27 pregnancies were interviewed. Participants were motivated to enroll in the study to find out more about their fetus' condition and prepare for the future. The waiting period was a time of significant anxiety for participants. Most participants felt relief and closure upon receiving results, regardless of the category of result, and had a clear understanding of the implications of the results. Conclusion Participants' experiences with pGS were often intertwined with the experience of having a fetus with an abnormality. Participants were satisfied with the decision to participate in research and the support they received from the healthcare team, although waiting for results was associated with anxiety. The healthcare team plays an integral role in setting expectations and validating feelings of anxiety, fear and uncertainty.

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Variants of uncertain significance in prenatal microarrays: a retrospective cohort study

Cited by 13 publications

References 22 publications

Perinatal outcomes and genomic characteristics of fetal copy number variants: An individual record linkage study of 713 pregnancies

Perinatal outcomes and genomic characteristics of fetal copy number variants: An individual record linkage study of 713 pregnancies

Microdeletions and microduplications linked to severe congenital disorders in infertile men

Information is power: The experiences, attitudes and needs of individuals who chose to have prenatal genomic sequencing for fetal anomalies

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