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Uncovering Disease-Associated SVA Insertions Missed by Routine Clinical Testing

Laboratory Genetics and Genomics
  • Primary Categories:
    • Basic Research
  • Secondary Categories:
    • Basic Research
Introduction:
Introduction: SINE-VNTR-Alu (SVA) elements are a class of composite retrotransposons that are active in the human genome. These elements can insert themselves into new genomic locations, potentially disrupting gene function and regulation, or may affect gene function by altering splicing or expression. Structural variations (SVs) caused by SVA insertions are underrepresented or not fully resolved in population databases due to technical challenges in detection, especially with short-read sequencing technologies. This underrepresentation hampers our understanding of their contribution to genetic disorders, true allele frequencies, and their impact to recessive conditions.

Methods:
Methods: We curated a list of rare SVA insertions likely to affect OMIM genes that were annotated in population databases. Their impact on gene function was predicted based on their location relative to coding regions, regulatory elements, and splice sites. We then identified insertions present in individuals from the 1000 Genomes Project who carry these insertions and performed long-read RNA sequencing to determine their impact on gene expression or splicing.

Results:
Results: We identified 4,948 SVA insertions with an allele frequency < 0.1% that may impact the function of an OMIM gene. Many of these insertions are located within genes or regulatory regions, suggesting potential impacts on gene expression and function. Specifically, we confirmed that our list contained previously reported pathogenic SVA insertions, including insertions in TAF1, LRIG2, and ASPA. Analysis of long-read RNA sequencing data allowed us to predict the impact of SVA insertions on gene expression or splicing in cell lines. 

SVA_E insertion in intron 32 of the TAF1 gene which has been associated with altered splicing and aberrant expression of TAF1. The SVA_E insertion in TAF1 was found to be the most common genetic cause of XDP in affected populations, particularly in individuals of Filipino descent, where the disease is more prevalent.

Conclusion:
Conclusions: SVA insertions represent a significant source of genetic variation with the potential to disrupt gene function and contribute to disease pathology. The underrepresentation or incomplete annotation of these elements in population databases poses challenges for variant interpretation in clinical genomics. Our study underscores the importance of incorporating SVA insertion analysis into genomic studies and highlights the need for comprehensive databases that include these elements. By improving the detection and annotation of SVA insertions, we can enhance our understanding of their role in genetic disorders and improve diagnostic outcomes. This research advances our knowledge of how mobile genetic elements like SVA insertions contribute to human disease. The development of methods to detect and analyze these insertions will facilitate better variant filtering and prioritization in clinical settings. Ultimately, this work contributes to more accurate genetic diagnoses and paves the way for targeted therapies for individuals affected by childhood-onset neurodegenerative disorders linked to SVA insertions.

Agenda

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