Uncovering recurrent microdeletion syndromes and subtelomeric deletions/duplications through non‐selective application of a MLPA‐based extended prenatal panel in routine prenatal diagnosis

Konialis, Christopher; Hagnefelt, Birgitta; Sevastidou, Sophia; Karapanou, Sophia; Pispili, Katerina; Markaki, Aggeliki; Pangalos, Constantinos

doi:10.1002/pd.2750

Cited by 13 publications

(19 citation statements)

References 32 publications

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“…While pregnancies found to have increased NT/nuchal fold or cystic hygroma had the highest rate of aneuploidy (30.9%), we did not detect any microdeletions or microduplications in this group. Some reports suggest that this ultrasound abnormality is not associated with an increased risk for submicroscopic chromosome abnormalities [30,[32][33][34] , but other studies have found such abnormalities using microarrays or other molecular tests, including the identification of some of the syndromes on our panel, such as 22q11.21 microdeletions [29,[35][36][37] .…”

Section: Discussionmentioning

confidence: 88%

Experience Using a Rapid Assay for Aneuploidy and Microdeletion/Microduplication Detection in over 2,900 Prenatal Specimens

Sa²,

Hummel³

et al. 2014

Fetal Diagn Ther

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Background: While microarray testing can identify chromosomal abnormalities missed by karyotyping, its prenatal use is often avoided in low-risk pregnancies due to the possible identification of variants of uncertain significance (VOUS). Methods: We tested 2,970 prenatal samples of all referral indications using a rapid BACs-on-Beads-based assay with probes for sex chromosomes, common autosomal aneuploidies, and 20 microdeletion/microduplication syndromes, designed as an alternative to microarray in low-risk pregnancies and an alternative to rapid aneuploidy testing in pregnancies also undergoing microarray analysis. Results: Interpretable results were obtained in 2,940 cases (99.0%), with 89% receiving results in 1 day. Aneuploidies were detected in 7.3% and partial chromosome abnormalities in 0.45% (n = 13), including 5 referred for maternal age, abnormal maternal serum screen, or isolated ultrasound markers. The added detection above karyotype was 1 in 745 in lower-risk cases with normal ultrasounds or isolated ultrasound markers/increased nuchal measurements and 1 in 165 for fetuses with structural/growth abnormalities. Neither false negatives nor false positives were found within test limitations. Female polyploidy could not be detected, while polyploidies with Y chromosomes were suspected and confirmed through additional analysis. Conclusion: When combined with karyotyping, this assay provides increased interrogation of specific chromosomal regions, while limiting VOUS identification.

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Section: Discussionmentioning

confidence: 88%

Experience Using a Rapid Assay for Aneuploidy and Microdeletion/Microduplication Detection in over 2,900 Prenatal Specimens

Sa²,

Hummel³

et al. 2014

Fetal Diagn Ther

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“…The same methods have also been used to identify larger chromosomal rearrangements, including those affecting subtelomeric regions. 2,3 Array comparative genomic hybridization (CGH) has proven to be a powerful tool for copy number analysis but has been used mostly for cytogenetic analysis to detect large genomic deletions and duplications that extend hundreds of kilobases to megabases.…”

Section: Introductionmentioning

confidence: 99%

Exon-level array CGH in a large clinical cohort demonstrates increased sensitivity of diagnostic testing for Mendelian disorders

Aradhya¹,

Lewis²,

Bonaga³

et al. 2012

Genetics in Medicine

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Purpose: Mendelian disorders are most commonly caused by mutations identifiable by DNA sequencing. Exonic deletions and duplications can go undetected by sequencing, and their frequency in most Mendelian disorders is unknown. methods:We designed an array comparative genomic hybridization (CGH) test with probes in exonic regions of 589 genes. Targeted testing was performed for 219 genes in 3,018 patients. We demonstrate for the first time the utility of exon-level array CGH in a large clinical cohort by testing for 136 autosomal dominant, 53 autosomal recessive, and 30 X-linked disorders.Results: Overall, 98 deletions and two duplications were identified in 53 genes, corresponding to a detection rate of 3.3%. Approximately 40% of positive findings were deletions of only one or two exons. A high frequency of deletions was observed for several autosomal dominant disorders, with a detection rate of 2.9%. For autosomal recessive disorders, array CGH was usually performed after a single mutation was identified by sequencing. Among 138 individuals tested for recessive disorders, 10.1% had intragenic deletions. For X-linked disorders, 3.5% of 313 patients carried a deletion or duplication.conclusion: Our results demonstrate that exon-level array CGH provides a robust option for intragenic copy number analysis and should routinely supplement sequence analysis for Mendelian disorders. 2012:14(6):594-603 Genet Med

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“…In an effort to increase the detection level of clinically important chromosomal abnormalities in PCD in a cost-effective and timely manner, we previously described [26] the detection of subtelomeric imbalances of all chromosomes coupled to the targeted detection of 23 recurrent microdeletion syndromes in the course of routine prenatal diagnosis, irrespective of indications. Through the combined use of standard karyotype analysis and MLPA assays, we applied this extended prenatal panel (EPP) to 1,550 cases requesting PCD for the usual indications and this was the first published report describing the relatively frequent occurrence of recurrent microdeletion/microduplication syndromes and subtelomeric aberrations in a large series of classical PCD cases, without any indication bias.…”

Section: Resultsmentioning

confidence: 99%

“…First, from cumulative data from both our MLPA and aCGH series as well as from several other studies [21,26,47,48,49], we have learned beyond doubt that clinically significant chromosomal abnormalities not detectable by conventional karyotype analysis constitute, on average, no less than 0.6-0.8% of all cases in a PCD population irrespective of indication and ∼0.6% - 1/175 of cases with AMA. As these sub-microscopic chromosomal abnormalities are not associated with AMA and, with few exceptions, are also not picked-up by any existing prenatal screening protocols, it would appear logical to assume that their frequency constitutes a new and important universal minimum baseline risk of 0.6-0.8% (∼1/140) applicable to all pregnancies.…”

Section: Discussionmentioning

confidence: 99%

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Dilemmas in Prenatal Chromosomal Diagnosis Revealed Through a Single Center's 30 Years' Experience and 90,000 Cases

2015

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Introduction: The aim of this article is to provide a perspective of prenatal chromosomal diagnosis (PCD) derived from a single center's evolving experience from ∼90,000 consecutive prenatal cases and to highlight important issues and current dilemmas. Materials and Methods: Prenatal cases in this study (1985-2013) were referred for various indications, and PCD was performed by standard karyotype in 84,255 cases, multiplex ligation-dependent probe amplification (MLPA) panel in 3,010 cases and standalone array comparative genomic hybridization (aCGH) in 3,122 cases. Results: Classic karyotype revealed 1.7 and 7.9% of pathological cases in amniotic fluid and CVS samples, respectively, with common aneuploidies accounting for 59.6 and 64.3% of the total abnormal. Molecular approaches increased the diagnostic yield by 0.6% for MLPA and 1.6% for aCGH, uncovering pathogenic chromosomal abnormalities undetectable by karyotype analysis. Conclusions: Current molecular diagnostic capabilities and the recent introduction of noninvasive prenatal testing (NIPT) point to one current major dilemma in PCD, with serious implications in genetic counseling, relating on the one hand to reaping the benefits from the high detection rate afforded through aCGH but accepting an invasive risk, and on the other hand, offering a lower detection rate practically only for Down syndrome, with minimal invasive risk.

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Uncovering recurrent microdeletion syndromes and subtelomeric deletions/duplications through non‐selective application of a MLPA‐based extended prenatal panel in routine prenatal diagnosis

Abstract: Our data represent the largest published series involving this type of genomic analysis in routine prenatal diagnosis, without indication bias. The panel increases significantly the diagnostic yield of conventional PCD and does not pose interpretation problems.

Cited by 13 publications

References 32 publications

Experience Using a Rapid Assay for Aneuploidy and Microdeletion/Microduplication Detection in over 2,900 Prenatal Specimens

Experience Using a Rapid Assay for Aneuploidy and Microdeletion/Microduplication Detection in over 2,900 Prenatal Specimens

Exon-level array CGH in a large clinical cohort demonstrates increased sensitivity of diagnostic testing for Mendelian disorders

Dilemmas in Prenatal Chromosomal Diagnosis Revealed Through a Single Center's 30 Years' Experience and 90,000 Cases

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