Investigation of a Pathogenic Inversion in UNC13D and Comprehensive Analysis of Chromosomal Inversions Across Diverse...

Area of Science:

• Genetics
• Genomics
• Bioinformatics

Background:

• Inversions are significant structural variants (SVs) implicated in genetic diseases.
• Detecting and interpreting inversions remains a major challenge in genetic analysis.
• Publicly available SV datasets have improved inversion exploration but lack cross-comparison.

Purpose of the Study:

• To investigate the characteristics of potentially pathogenic inversions in public datasets.
• To compare inversion detection across multiple large-scale datasets.
• To understand the role of inversions in rare genetic diseases.

Main Methods:

• Analysis of a proband with familial hemophagocytic lymphohistiocytosis type-3 and a novel inversion in UNC13D.
• Cross-dataset comparison of inversions using gnomAD, DGV, 1KGP, and Human Genome Structural Variation Consortium data.
• Classification of inversions disrupting protein-coding genes based on OMIM phenotypes.

Main Results:

• A pathogenic inversion in UNC13D was identified in a rare disease patient.
• 98.9% of inversions in gnomAD are rare; 5% disrupt OMIM-associated protein-coding genes.
• Comparative analysis revealed dataset-specific inversion characteristics, suggesting detection biases.
• Most OMIM genes disrupted by inversions are linked to autosomal recessive phenotypes.

Conclusions:

• Inversions, especially when in trans with other variants, can be hidden causes of monogenic diseases.
• Identifying low-frequency inversions is essential for rare disease diagnosis.
• This study provides insights into the molecular characteristics of inversions and their clinical significance.