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
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 -