Small Copy Number Neutral Intrachromosomal Translocation of PAX6 and Aniridia

Area of Science:

• Genetics
• Genomics
• Molecular Biology

Background:

• Classic aniridia affects 5-10% of individuals who lack a molecular diagnosis after standard PAX6 gene variant testing.
• Unexplained aniridia cases necessitate advanced diagnostic approaches to identify underlying genetic causes.

Purpose of the Study:

• To utilize optical genome mapping (OGM) and long-read whole-genome sequencing (lrWGS) for diagnosing aniridia in a patient with prior negative genetic testing.
• To investigate the utility of OGM and lrWGS in identifying complex structural variants impacting gene expression.

Main Methods:

• A 16-year-old male patient with classic aniridia underwent OGM and lrWGS.
• DNA was analyzed following negative results from sequencing, copy number analysis, and short-read whole-genome sequencing (srWGS) of the PAX6 gene and its regulatory regions.

Main Results:

• OGM detected a 55-kb deletion at 11p13 involving PAX6 and ELP4, with translocation to 11q21.
• lrWGS confirmed the deletion and translocation, revealing separation of the PAX6 coding sequence from its regulatory region.
• The identified structural variant disrupted PAX6 expression, explaining the patient's aniridia phenotype.

Conclusions:

• OGM and lrWGS successfully identified a novel, small intrachromosomal rearrangement at the PAX6 locus in an aniridia patient.
• This structural variant, potentially missed by srWGS due to its size and balanced nature, highlights the importance of advanced sequencing methods.
• These findings underscore the role of OGM and lrWGS in diagnosing genetic disorders with complex genomic alterations.