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 Bryndorf; Claus Hansen; Michael E. Talkowski; Mads Bak; Niels Tommerup; Iben Bache

doi:10.1016/j.ajhg.2018.04.005

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

15 Citations (Scopus)

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 language	English
Journal	American Journal of Human Genetics
Volume	102
Issue number	6
Pages (from-to)	1090-1103
Number of pages	14
ISSN	0002-9297
DOIs	https://doi.org/10.1016/j.ajhg.2018.04.005
Publication status	Published - 2018

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

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Halgren, C., Nielsen, N. M., Nazaryan-Petersen, L., Silahtaroglu, A., Collins, R. L., Lowther, C., Kjaergaard, S., Frisch, M., Kirchhoff, M., Brøndum-Nielsen, K., Lind-Thomsen, A., Mang, Y., El-Schich, Z., Boring, C. A., Mehrjouy, M. M., Jensen, P. K. A., Fagerberg, C., Krogh, L. N., Hansen, J., ... 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

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 et al.
In: American Journal of Human Genetics, Vol. 102, No. 6, 2018, p. 1090-1103.

Research output: Contribution to journal › Journal article › Research › peer-review

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

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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 = "balanced chromosomal rearrangement, clinical recommendations, de novo, inversion, long-term follow-up, mate-pair mapping, morbidity risk, neurodevelopmental/-psychiatric disorders, prenatal diagnosis, reciprocal translocation",

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",

year = "2018",

doi = "10.1016/j.ajhg.2018.04.005",

language = "English",

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pages = "1090--1103",

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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

Y1 - 2018

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 - balanced chromosomal rearrangement

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

U2 - 10.1016/j.ajhg.2018.04.005

DO - 10.1016/j.ajhg.2018.04.005

M3 - Journal article

C2 - 29805044

AN - SCOPUS:85047187634

SN - 0002-9297

VL - 102

SP - 1090

EP - 1103

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 6

ER -

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

Abstract

Keywords

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