Genotype-Phenotype Correlation Through Breakpoint Characterization of a Genomically Balanced Complex Chromosomal...

Molecular characterization of balanced complex chromosomal rearrangements (CCR) aids in understanding the pathophysiological mechanism and corresponding genotype-phenotype correlations. The present case describes a male child with intellectual disability, developmental delay, and dysmorphism. A thorough and sequential genetic evaluation using karyotyping, fluorescence in situ hybridization (FISH), chromosomal microarray (CMA), and long read sequencing (LRS) identified a genomically balanced CCR. The CCR involved eight chromosomes, the largest to be documented till date for chromoanagenesis and being balanced despite the high level of complex chromosomal involvement. Translocations accounted for the majority of the rearrangements along with an insertion, inversion, and a small deletion likely driven by chromoplexy. Although the CCR was genomically balanced, it may still result in functionally significant genomic consequences including gene disruptions, gene fusions, and position effects. Long read whole genome sequencing using PacBio was used for breakpoint characterization that revealed three protein-coding genes to be disrupted, namely, NLGN4X, LAMA4, and ALG6. Of these, a candidate association was observed for the NLGN4X gene with the intellectual disability phenotype reported in the proband, which is likely due to disruption of transcription and nonsense mediated decay. We show combinatorial application of advanced genomic technologies with orthogonal cytogenetic techniques in delineating balanced CCRs and understanding the biological and potential clinical implications of balanced yet functionally disruptive CCRs.