Structural Chromosomal Rearrangements Require Nucleotide-Level Resolution: Lessons from Next-Generation Sequencing in...

Area of Science:

• Genetics
• Genomics
• Prenatal Diagnostics

Background:

• Next-generation sequencing enables precise detection of balanced chromosomal rearrangements in prenatal diagnostics.
• De novo balanced chromosomal rearrangements in newborns are linked to increased congenital abnormalities.
• Accurate interpretation of rearrangement breakpoints is crucial for predicting phenotypic outcomes and guiding perinatal care.

Purpose of the Study:

• To evaluate the utility of genomic sequencing in detecting and interpreting balanced chromosomal rearrangements in prenatal samples.
• To correlate sequencing findings of structural rearrangements with topological domains and gene regulation.
• To compare the diagnostic power of this molecular approach against standard methods like microarray and cfDNA screening.

Main Methods:

• Genomic sequencing was performed on ten prenatal subjects with balanced chromosomal rearrangements.
• Breakpoint locations were analyzed in relation to topologically associated domains (TADs).
• Results were compared with microarray analyses and clinical phenotypes.

Main Results:

• Sequencing identified rearrangements missed by microarray and cfDNA screening.
• Findings correlated with pregnancy outcomes: 5/10 with adverse outcomes, 3/10 with healthy newborns.
• Two cases were terminated before phenotype-genotype correlation could be established.

Conclusions:

• Clinical interpretation of structural rearrangements must include regulatory genomic domains, not just gene interruptions.
• This molecular approach provides superior information for genetic counseling compared to cfDNA and microarray.
• Integrating genomic sequencing enhances prenatal diagnosis and prediction of phenotypic outcomes.