Isochromosome 21q is overrepresented among false-negative cell-free DNA prenatal screening results involving Down syndrome

False-negative cell-free DNA (cfDNA) screening results involving Down syndrome are rare, but have high clinical impact on patients and their healthcare providers. Understanding the biology behind these results may allow for improved diagnostic follow-up and counseling. In 5 different centers offerin...

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Published inEuropean journal of human genetics : EJHG Vol. 26; no. 10; pp. 1490 - 1496
Main Authors Huijsdens-van Amsterdam, Karin, Page-Christiaens, Lieve, Flowers, Nicola, Bonifacio, Michael D, Ellis, Katie M Battese, Vogel, Ida, Vestergaard, Else Marie, Miguelez, Javier, de Carvalho, Mario Henrique Burlacchini, Sistermans, Erik A, Pertile, Mark D
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Published England Nature Publishing Group 01.10.2018
Springer International Publishing
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Abstract False-negative cell-free DNA (cfDNA) screening results involving Down syndrome are rare, but have high clinical impact on patients and their healthcare providers. Understanding the biology behind these results may allow for improved diagnostic follow-up and counseling. In 5 different centers offering cfDNA prenatal screening, 9 false-negative results were documented in 646 confirmed cases of trisomy 21; a false-negative rate of 1.4% (95% CI, 0.7-2.6). False-negative results included 4 cases of classical trisomy 21 and 5 cases with a de novo 21q;21q rearrangement. Two out of five rearrangements had molecular studies and were confirmed as isochromosomes. When combined with reports from the cfDNA screening literature, 8 out of 29 (28%) Down syndrome cases with a false-negative "non-invasive prenatal test" (NIPT) were associated with a 21q;21q rearrangement, compared with 2% reported in live born children with Down syndrome. In our laboratory series, evidence for placental or fetal mosaicism was present in 3 out of 3 true-positive cases involving a 21q;21q rearrangement and was confirmed in one false-negative case where placental material was available for study. Isochromosome 21q rearrangements are thus overrepresented among false-negative cfDNA screening results involving Down syndrome. Postzygotic isochromosome formation leading to placental mosaicism provides a biological cause for the increased prevalence of these rearrangements among false-negative cases. For clinical practice, a low trisomic fraction (z-score or equivalent measure) relative to the fetal fraction suggests placental mosaicism. Care should be taken as these cases may not reflect confined placental mosaicism, but rather full trisomy in the presence of a placenta containing normal cells.
AbstractList False-negative cell-free DNA (cfDNA) screening results involving Down syndrome are rare, but have high clinical impact on patients and their healthcare providers. Understanding the biology behind these results may allow for improved diagnostic follow-up and counseling. In 5 different centers offering cfDNA prenatal screening, 9 false-negative results were documented in 646 confirmed cases of trisomy 21; a false-negative rate of 1.4% (95% CI, 0.7–2.6). False-negative results included 4 cases of classical trisomy 21 and 5 cases with a de novo 21q;21q rearrangement. Two out of five rearrangements had molecular studies and were confirmed as isochromosomes. When combined with reports from the cfDNA screening literature, 8 out of 29 (28%) Down syndrome cases with a false-negative “non-invasive prenatal test” (NIPT) were associated with a 21q;21q rearrangement, compared with 2% reported in live born children with Down syndrome. In our laboratory series, evidence for placental or fetal mosaicism was present in 3 out of 3 true-positive cases involving a 21q;21q rearrangement and was confirmed in one false-negative case where placental material was available for study. Isochromosome 21q rearrangements are thus overrepresented among false-negative cfDNA screening results involving Down syndrome. Postzygotic isochromosome formation leading to placental mosaicism provides a biological cause for the increased prevalence of these rearrangements among false-negative cases. For clinical practice, a low trisomic fraction (z-score or equivalent measure) relative to the fetal fraction suggests placental mosaicism. Care should be taken as these cases may not reflect confined placental mosaicism, but rather full trisomy in the presence of a placenta containing normal cells.
False-negative cell-free DNA (cfDNA) screening results involving Down syndrome are rare, but have high clinical impact on patients and their healthcare providers. Understanding the biology behind these results may allow for improved diagnostic follow-up and counseling. In 5 different centers offering cfDNA prenatal screening, 9 false-negative results were documented in 646 confirmed cases of trisomy 21; a false-negative rate of 1.4% (95% CI, 0.7–2.6). False-negative results included 4 cases of classical trisomy 21 and 5 cases with a de novo 21q;21q rearrangement. Two out of five rearrangements had molecular studies and were confirmed as isochromosomes. When combined with reports from the cfDNA screening literature, 8 out of 29 (28%) Down syndrome cases with a false-negative “non-invasive prenatal test” (NIPT) were associated with a 21q;21q rearrangement, compared with 2% reported in live born children with Down syndrome. In our laboratory series, evidence for placental or fetal mosaicism was present in 3 out of 3 true-positive cases involving a 21q;21q rearrangement and was confirmed in one false-negative case where placental material was available for study. Isochromosome 21q rearrangements are thus overrepresented among false-negative cfDNA screening results involving Down syndrome. Postzygotic isochromosome formation leading to placental mosaicism provides a biological cause for the increased prevalence of these rearrangements among false-negative cases. For clinical practice, a low trisomic fraction ( z -score or equivalent measure) relative to the fetal fraction suggests placental mosaicism. Care should be taken as these cases may not reflect confined placental mosaicism, but rather full trisomy in the presence of a placenta containing normal cells.
Author Vogel, Ida
Ellis, Katie M Battese
Flowers, Nicola
Huijsdens-van Amsterdam, Karin
Bonifacio, Michael D
Miguelez, Javier
Vestergaard, Else Marie
de Carvalho, Mario Henrique Burlacchini
Sistermans, Erik A
Page-Christiaens, Lieve
Pertile, Mark D
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Snippet False-negative cell-free DNA (cfDNA) screening results involving Down syndrome are rare, but have high clinical impact on patients and their healthcare...
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SubjectTerms Cell-Free Nucleic Acids - genetics
Children
Chromosomes, Human, Pair 21 - genetics
Deoxyribonucleic acid
DNA
Down syndrome
Down Syndrome - diagnosis
Down Syndrome - genetics
Down Syndrome - pathology
Down's syndrome
Female
Fetuses
Genetic screening
Humans
Isochromosomes
Isochromosomes - genetics
Karyotyping
Mosaicism
Placenta
Placenta - cytology
Pregnancy
Prenatal diagnosis
Prenatal Diagnosis - standards
Trisomy
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Title Isochromosome 21q is overrepresented among false-negative cell-free DNA prenatal screening results involving Down syndrome
URI https://www.ncbi.nlm.nih.gov/pubmed/29899373
https://www.proquest.com/docview/2104154141
https://search.proquest.com/docview/2055616831
https://pubmed.ncbi.nlm.nih.gov/PMC6138668
Volume 26
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