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

Christina Halgren, Nete M. Nielsen, Lusine Nazaryan-Petersen, Asli Silahtaroglu, Ryan L. Collins, Chelsea Lowther, Susanne Kjaergaard, Morten Frisch, Maria Kirchhoff, Karen Brøndum-Nielsen, Allan Lind-Thomsen, Yuan Mang, Zahra El-Schich, Claire A. Boring, Mana M. Mehrjouy, Peter K.A. Jensen, Christina Fagerberg, Lotte N. Krogh, Jan Hansen, Thue BryndorfClaus Hansen, Michael E. Talkowski, Mads Bak, Niels Tommerup, Iben Bache*

*Corresponding author for this work

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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.

Original languageEnglish
JournalAmerican Journal of Human Genetics
Volume102
Issue number6
Pages (from-to)1090-1103
ISSN0002-9297
DOIs
Publication statusPublished - 7. Jun 2018

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First Pregnancy Trimester
Routine Diagnostic Tests
Registries
Research Design
Control Groups

Keywords

  • balanced chromosomal rearrangement
  • clinical recommendations
  • de novo
  • inversion
  • long-term follow-up
  • mate-pair mapping
  • morbidity risk
  • neurodevelopmental/-psychiatric disorders
  • prenatal diagnosis
  • reciprocal translocation
  • Chromosome Breakpoints
  • Humans
  • RNA, Long Noncoding/genetics
  • Time Factors
  • Karyotyping
  • Female
  • Risk Factors
  • Sequence Analysis, DNA
  • Pregnancy
  • Prenatal Diagnosis/methods
  • Conserved Sequence/genetics
  • Chromosome Aberrations
  • Genome, Human
  • Cohort Studies
  • Evolution, Molecular

Cite this

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.
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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.",
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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",
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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

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

In: American Journal of Human Genetics, Vol. 102, No. 6, 07.06.2018, p. 1090-1103.

Research output: Contribution to journalJournal articleResearchpeer-review

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

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.

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KW - clinical recommendations

KW - de novo

KW - inversion

KW - long-term follow-up

KW - mate-pair mapping

KW - morbidity risk

KW - neurodevelopmental/-psychiatric disorders

KW - prenatal diagnosis

KW - reciprocal translocation

KW - Chromosome Breakpoints

KW - Humans

KW - RNA, Long Noncoding/genetics

KW - Time Factors

KW - Karyotyping

KW - Female

KW - Risk Factors

KW - Sequence Analysis, DNA

KW - Pregnancy

KW - Prenatal Diagnosis/methods

KW - Conserved Sequence/genetics

KW - Chromosome Aberrations

KW - Genome, Human

KW - Cohort Studies

KW - Evolution, Molecular

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U2 - 10.1016/j.ajhg.2018.04.005

DO - 10.1016/j.ajhg.2018.04.005

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JO - American Journal of Human Genetics

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