Forskning
Udskriv Udskriv
Switch language
Region Hovedstaden - en del af Københavns Universitetshospital
Udgivet

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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

DOI

  1. Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  2. Complex Compound Inheritance of Lethal Lung Developmental Disorders Due to Disruption of the TBX-FGF Pathway

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  3. Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  4. Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  1. Tissue variations of mosaic genome-wide paternal uniparental disomy and phenotype of multi-syndromal congenital hyperinsulinism

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  2. Haploinsufficiency of ARHGAP42 is associated with hypertension

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  3. Genomisk medicin til præimplantations-, 
præ- og postnatal diagnostik

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Vis graf over relationer

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.

OriginalsprogEngelsk
TidsskriftAmerican Journal of Human Genetics
Vol/bind102
Udgave nummer6
Sider (fra-til)1090-1103
Antal sider14
ISSN0002-9297
DOI
StatusUdgivet - 7 jun. 2018

ID: 56076288