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.

Insertional translocation involving an additional nonchromothriptic chromosome in constitutional chromothripsis: Rule or exception?

“…We checked TADs possibly disrupted by the breakpoints of chromothripsis in neurogenic precursor cells (H1‐NPC; Dixon et al, ; a neurodevelopmental phenotype was present in the probands of cases 1 and 3) and lymphoblastoid cells (GM12878; Lieberman‐Aiden et al, ) by using web‐based 3D Genome Browser (Rao et al, ). As in recently published study (Halgren et al, ), we also collected the probability of loss‐of‐function intolerance (pLI) according to the Exome Aggregation Consortium (ExAC; Lek et al, ), with high pLI scores (pLI ≥ 0.9) indicating genes extremely intolerant to loss of function, and the corresponding haploinsufficiency (HI) scores (Huang, Lee, Marcotte, & Hurles, ) (DECIPHER) with percentages between 0% and 10% indicating genes that are more likely to exhibit haploinsufficiency. Genes at disrupted TADs, which are known to be associated with autosomal dominant disease (OMIM), are also indicated.…”

Pandora's pregnancy: NIPT, CMA, and genome sequencing—A new era for prenatal genetic testing

“…While counselees might have construed results concerning chromosomal conditions as binary-either positive or negative-prenatal karyotyping also had its share of uncertainty. 5 While there are studies estimating the morbidity risks associated with certain chromosomal rearrangements identified via karyotyping, 6 it is hard to find studies indicating a general number representing the overall prevalence of uncertain findings found in karyotyping. This is in contrast to the well-documented incidence of findings of uncertain significance in the new methods (for instance, a prevalence of approximately 1%-2% of VUS in CMA [7][8][9] ).…”

Mapping of breakpoints in balanced chromosomal translocations by shallow whole-genome sequencing points toEFNA5,BAHD1andPPP2R5Eas novel candidates for genes causing human Mendelian disorders

“…De novo BCTs have a frequency of 1 per 2000 live births 2. Most individuals with BCTs are healthy, nonetheless in up to 26.8% of cases, BCTs are associated with clinical pathology 3. Symptomatic BCTs provide a unique opportunity to identify the causative genetic mechanism as it is likely that such a mechanism is directly related to genome damage inflicted by the breakpoint(s).…”