Summary: Researchers report fetuses with a rare chromosomal aberration have a 20% increased risk of being diagnosed with a developmental disorder.
Source: University of Copenhagen.
Fetuses with a specific, rare chromosomal aberration have a 20 per cent risk of a developmental disorder or another brain disorder, a new study conducted at the University of Copenhagen reveals. The findings may provide personalised diagnostics and counselling for these pregnant women.
These chromosomal aberrations are seen in the fetus in one out of 2,000 pregnant women. Until now, when such an aberration has been found, the medical doctors have told the pregnant woman that the foetus’ risk of developing congenital malformations is 6-9 per cent.
‘We have identified all the people who, as fetuses, were diagnosed with such a chromosomal aberration in Denmark, and we can see that they more often have developed a disease. The previous study, which found a risk of 6-9 per cent, mainly looked at congenital malformations and did not include neurocognitive diseases such as autism and mental retardation, which often emerge at a later stage. We have therefore been unaware of the extent of the total risk’, says one of the authors of the study, Iben Bache, who is associate professor at the Department of Cellular and Molecular Medicine at the Faculty of Health and Medical Sciences and medical doctor at the Department of Clinical Genetics at Rigshospitalet.
Chromosomal Material that Has been Exchanged
’We call these aberrations balanced chromosomal rearrangements, because all the genetic material is still there. There is neither a loss nor a gain of genetic material. The problem is that parts of the genetic material have been exchanged, and that might have caused disruption of an important gene’, says Iben Bache.
The study is the largest systematic survey of these rare chromosomal aberrations in foetuses, and it also evaluates the methods that can be used for examining them. These chromosomal abnormalities are diagnosed through chorionic villus sampling or amniocentesis by classical chromosomal analysis, where the genetic material is examined in a microscope. This method has been used for the last 40 years, and it is still the method used in most pregnancies globally.
However, in Danish hospitals the method is increasingly being replaced with another method, chromosomal microarray, which exclusively tests for loss and gain of the genetic material. Chromosomal microarray therefore cannot discover the rare balanced aberrations studied here. In contrast, the study reveals that modern genome sequencing in most cases will be able not only to detect these balanced chromosomal aberrations but also show whether genes have been damaged.
The study is a collaboration between researchers at the University of Copenhagen doing basic research, all clinical genetic departments in Denmark and the Department of Epidemiological Research at Statens Serum Institut. The researchers carefully examined the Danish health records to find everyone born with a de novo balanced chromosomal aberration since 1975. Each time they found a person with the aberration, they established a control group of five individuals with normal chromosomes, who had been born more or less at the same time by a mother of the same age.
The researchers then visited the majority of the persons to do a health examination and collect blood samples for modern genetic analyses. By comparing the health data of the group with the chromosomal aberrations and the control group, the researchers found two-three times higher risk of developing a neurocognitive disorder in the group with the chromosomal aberrations.
In addition, the researchers found that the new whole genome sequencing techniques are much better than any other techniques at assessing the health effect of a balanced chromosomal aberration. This is the conclusion after almost identical assessments made by two independent research groups, including a group from the Harvard Medical School.
‘We have not known which analyses to use to discriminate the foetuses that will be healthy from those that will eventually develop disorders. Our study shows that by using the new sequencing technologies we can in fact discriminate in a number of cases. This may greatly affect the diagnosing and counselling of pregnant women carrying foetuses with this specific type of chromosomal aberration in the future’, says Iben Bache.
Funding: The study was funded by the Lundbeck Foundation and originally emanated from a grant from the Danish National Research Foundation.
Source: University of Copenhagen
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Original Research: Abstract for “Risks and Recommendations in Prenatally Detected De Novo Balanced Chromosomal Rearrangements from Assessment of Long-Term Outcomes” by 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 in American Journal of Human Genetics. Published May 24 2018.
Risks and Recommendations in Prenatally Detected De Novo Balanced Chromosomal Rearrangements from Assessment of Long-Term Outcomes
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.