학술논문
Risks and Recommendations in Prenatally Detected De Novo Balanced Chromosomal Rearrangements from Assessment of Long-Term Outcomes.
Document Type
Article
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
Source
Subject
*CHROMOSOMES
*CELL nuclei
*NEUROBEHAVIORAL disorders
*HETEROCHROMATIN
*DISEASES
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Language
ISSN
0002-9297
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. [ABSTRACT FROM AUTHOR]