Genotype-Phenotype Correlation Through Breakpoint Characterization of a Genomically Balanced Complex Chromosomal Rearrangement Using Long Read Sequencing

Long-read sequencing for breakpoint characterization of an 8-chromosome CCR, unsolvable by conventional techniques

A boy with intellectual disability, developmental delay, and dysmorphic features is investigated by karyotyping, FISH, CMA, then long-read sequencing, which characterizes a balanced complex chromosomal rearrangement (CCR) involving 8 chromosomes. Breakpoint analysis identifies three disrupted genes: NLGN4X (neuroligin, linked to autism spectrum disorder and ID), LAMA4, and ALG6. This case illustrates the superiority of long-read sequencing for resolving CCRs that escape conventional techniques, establishing a precise genotype-phenotype correlation.

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Balanced CCRs remain one of the blind spots of conventional genomic diagnosis: invisible to CMA, partially visible on karyotype. This paradigmatic case justifies integrating long-read sequencing as a second-tier approach for NDD or congenital anomalies with complex karyotype or normal CMA.

Clinical impact: 2/3 · Evidence strength: 2/3 · Novelty: 2/2 · Sample size: 0/1 · Publication status: 1/1 → Total: 7/10