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Risks and Recommendations in Prenatally Detected De Novo Balanced Chromosomal Rearrangements from Assessment of Long-Term Outcomes

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Harvard

Halgren, C, Nielsen, NM, Nazaryan-Petersen, L, Silahtaroglu, A, Collins, RL, Lowther, C, Kjaergaard, S, Frisch, M, Kirchhoff, M, Brøndum-Nielsen, K, Lind-Thomsen, A, Mang, Y, El-Schich, Z, Boring, CA, Mehrjouy, MM, Jensen, PKA, Fagerberg, C, Krogh, LN, Hansen, J, Bryndorf, T, Hansen, C, Talkowski, ME, Bak, M, Tommerup, N & Bache, I 2018, 'Risks and Recommendations in Prenatally Detected De Novo Balanced Chromosomal Rearrangements from Assessment of Long-Term Outcomes' American Journal of Human Genetics, vol. 102, no. 6, pp. 1090-1103. https://doi.org/10.1016/j.ajhg.2018.04.005

APA

CBE

Halgren C, Nielsen NM, Nazaryan-Petersen L, Silahtaroglu A, Collins RL, Lowther C, Kjaergaard S, Frisch M, Kirchhoff M, Brøndum-Nielsen K, Lind-Thomsen A, Mang Y, El-Schich Z, Boring CA, Mehrjouy MM, Jensen PKA, Fagerberg C, Krogh LN, Hansen J, Bryndorf T, Hansen C, Talkowski ME, Bak M, Tommerup N, Bache I. 2018. Risks and Recommendations in Prenatally Detected De Novo Balanced Chromosomal Rearrangements from Assessment of Long-Term Outcomes. American Journal of Human Genetics. 102(6):1090-1103. https://doi.org/10.1016/j.ajhg.2018.04.005

MLA

Vancouver

Author

Halgren, Christina ; Nielsen, Nete M ; Nazaryan-Petersen, Lusine ; Silahtaroglu, Asli ; Collins, Ryan L ; Lowther, Chelsea ; Kjaergaard, Susanne ; Frisch, Morten ; Kirchhoff, Maria ; Brøndum-Nielsen, Karen ; Lind-Thomsen, Allan ; Mang, Yuan ; El-Schich, Zahra ; Boring, Claire A ; Mehrjouy, Mana M ; Jensen, Peter K A ; Fagerberg, Christina ; Krogh, Lotte N ; Hansen, Jan ; Bryndorf, Thue ; Hansen, Claus ; Talkowski, Michael E ; Bak, Mads ; Tommerup, Niels ; Bache, Iben. / Risks and Recommendations in Prenatally Detected De Novo Balanced Chromosomal Rearrangements from Assessment of Long-Term Outcomes. In: American Journal of Human Genetics. 2018 ; Vol. 102, No. 6. pp. 1090-1103.

Bibtex

@article{99a76709f43a47758afa9358e680df6e,
title = "Risks and Recommendations in Prenatally Detected De Novo Balanced Chromosomal Rearrangements from Assessment of Long-Term Outcomes",
abstract = "The 6{\%}-9{\%} risk of an untoward outcome previously established by Warburton for prenatally detected de novo balanced chromosomal rearrangements (BCRs) does not account for long-term morbidity. We performed long-term follow-up (mean 17 years) of a registry-based nationwide cohort of 41 individuals carrying a prenatally detected de novo BCR with normal first trimester screening/ultrasound scan. We observed a significantly higher frequency of neurodevelopmental and/or neuropsychiatric disorders than in a matched control group (19.5{\%} versus 8.3{\%}, p = 0.04), which was increased to 26.8{\%} upon clinical follow-up. Chromosomal microarray of 32 carriers revealed no pathogenic imbalances, illustrating a low prognostic value when fetal ultrasound scan is normal. In contrast, mate-pair sequencing revealed disrupted genes (ARID1B, NPAS3, CELF4), regulatory domains of known developmental genes (ZEB2, HOXC), and complex BCRs associated with adverse outcomes. Seven unmappable autosomal-autosomal BCRs with breakpoints involving pericentromeric/heterochromatic regions may represent a low-risk group. We performed independent phenotype-aware and blinded interpretation, which accurately predicted benign outcomes (specificity = 100{\%}) but demonstrated relatively low sensitivity for prediction of the clinical outcome in affected carriers (sensitivity = 45{\%}-55{\%}). This sensitivity emphasizes the challenges associated with prenatal risk prediction for long-term morbidity in the absence of phenotypic data given the still immature annotation of the morbidity genome and poorly understood long-range regulatory mechanisms. In conclusion, we upwardly revise the previous estimates of Warburton to a morbidity risk of 27{\%} and recommend sequencing of the chromosomal breakpoints as the first-tier diagnostic test in pregnancies with a de novo BCR.",
keywords = "Chromosome Aberrations, Chromosome Breakpoints, Cohort Studies, Conserved Sequence/genetics, Evolution, Molecular, Female, Genome, Human, Humans, Karyotyping, Pregnancy, Prenatal Diagnosis/methods, RNA, Long Noncoding/genetics, Risk Factors, Sequence Analysis, DNA, Time Factors",
author = "Christina Halgren and Nielsen, {Nete M} and Lusine Nazaryan-Petersen and Asli Silahtaroglu and Collins, {Ryan L} and Chelsea Lowther and Susanne Kjaergaard and Morten Frisch and Maria Kirchhoff and Karen Br{\o}ndum-Nielsen and Allan Lind-Thomsen and Yuan Mang and Zahra El-Schich and Boring, {Claire A} and Mehrjouy, {Mana M} and Jensen, {Peter K A} and Christina Fagerberg and Krogh, {Lotte N} and Jan Hansen and Thue Bryndorf and Claus Hansen and Talkowski, {Michael E} and Mads Bak and Niels Tommerup and Iben Bache",
note = "Copyright {\circledC} 2018 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.",
year = "2018",
month = "6",
day = "7",
doi = "10.1016/j.ajhg.2018.04.005",
language = "English",
volume = "102",
pages = "1090--1103",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "6",

}

RIS

TY - JOUR

T1 - Risks and Recommendations in Prenatally Detected De Novo Balanced Chromosomal Rearrangements from Assessment of Long-Term Outcomes

AU - Halgren, Christina

AU - Nielsen, Nete M

AU - Nazaryan-Petersen, Lusine

AU - Silahtaroglu, Asli

AU - Collins, Ryan L

AU - Lowther, Chelsea

AU - Kjaergaard, Susanne

AU - Frisch, Morten

AU - Kirchhoff, Maria

AU - Brøndum-Nielsen, Karen

AU - Lind-Thomsen, Allan

AU - Mang, Yuan

AU - El-Schich, Zahra

AU - Boring, Claire A

AU - Mehrjouy, Mana M

AU - Jensen, Peter K A

AU - Fagerberg, Christina

AU - Krogh, Lotte N

AU - Hansen, Jan

AU - Bryndorf, Thue

AU - Hansen, Claus

AU - Talkowski, Michael E

AU - Bak, Mads

AU - Tommerup, Niels

AU - Bache, Iben

N1 - Copyright © 2018 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

PY - 2018/6/7

Y1 - 2018/6/7

N2 - The 6%-9% risk of an untoward outcome previously established by Warburton for prenatally detected de novo balanced chromosomal rearrangements (BCRs) does not account for long-term morbidity. We performed long-term follow-up (mean 17 years) of a registry-based nationwide cohort of 41 individuals carrying a prenatally detected de novo BCR with normal first trimester screening/ultrasound scan. We observed a significantly higher frequency of neurodevelopmental and/or neuropsychiatric disorders than in a matched control group (19.5% versus 8.3%, p = 0.04), which was increased to 26.8% upon clinical follow-up. Chromosomal microarray of 32 carriers revealed no pathogenic imbalances, illustrating a low prognostic value when fetal ultrasound scan is normal. In contrast, mate-pair sequencing revealed disrupted genes (ARID1B, NPAS3, CELF4), regulatory domains of known developmental genes (ZEB2, HOXC), and complex BCRs associated with adverse outcomes. Seven unmappable autosomal-autosomal BCRs with breakpoints involving pericentromeric/heterochromatic regions may represent a low-risk group. We performed independent phenotype-aware and blinded interpretation, which accurately predicted benign outcomes (specificity = 100%) but demonstrated relatively low sensitivity for prediction of the clinical outcome in affected carriers (sensitivity = 45%-55%). This sensitivity emphasizes the challenges associated with prenatal risk prediction for long-term morbidity in the absence of phenotypic data given the still immature annotation of the morbidity genome and poorly understood long-range regulatory mechanisms. In conclusion, we upwardly revise the previous estimates of Warburton to a morbidity risk of 27% and recommend sequencing of the chromosomal breakpoints as the first-tier diagnostic test in pregnancies with a de novo BCR.

AB - The 6%-9% risk of an untoward outcome previously established by Warburton for prenatally detected de novo balanced chromosomal rearrangements (BCRs) does not account for long-term morbidity. We performed long-term follow-up (mean 17 years) of a registry-based nationwide cohort of 41 individuals carrying a prenatally detected de novo BCR with normal first trimester screening/ultrasound scan. We observed a significantly higher frequency of neurodevelopmental and/or neuropsychiatric disorders than in a matched control group (19.5% versus 8.3%, p = 0.04), which was increased to 26.8% upon clinical follow-up. Chromosomal microarray of 32 carriers revealed no pathogenic imbalances, illustrating a low prognostic value when fetal ultrasound scan is normal. In contrast, mate-pair sequencing revealed disrupted genes (ARID1B, NPAS3, CELF4), regulatory domains of known developmental genes (ZEB2, HOXC), and complex BCRs associated with adverse outcomes. Seven unmappable autosomal-autosomal BCRs with breakpoints involving pericentromeric/heterochromatic regions may represent a low-risk group. We performed independent phenotype-aware and blinded interpretation, which accurately predicted benign outcomes (specificity = 100%) but demonstrated relatively low sensitivity for prediction of the clinical outcome in affected carriers (sensitivity = 45%-55%). This sensitivity emphasizes the challenges associated with prenatal risk prediction for long-term morbidity in the absence of phenotypic data given the still immature annotation of the morbidity genome and poorly understood long-range regulatory mechanisms. In conclusion, we upwardly revise the previous estimates of Warburton to a morbidity risk of 27% and recommend sequencing of the chromosomal breakpoints as the first-tier diagnostic test in pregnancies with a de novo BCR.

KW - Chromosome Aberrations

KW - Chromosome Breakpoints

KW - Cohort Studies

KW - Conserved Sequence/genetics

KW - Evolution, Molecular

KW - Female

KW - Genome, Human

KW - Humans

KW - Karyotyping

KW - Pregnancy

KW - Prenatal Diagnosis/methods

KW - RNA, Long Noncoding/genetics

KW - Risk Factors

KW - Sequence Analysis, DNA

KW - Time Factors

U2 - 10.1016/j.ajhg.2018.04.005

DO - 10.1016/j.ajhg.2018.04.005

M3 - Journal article

VL - 102

SP - 1090

EP - 1103

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 6

ER -

ID: 56076288