Noncoding mutation in RPGRIP1 contributes to inherited retinal degenerations

Area of Science:

• Genetics
• Ophthalmology
• Molecular Biology

Background:

• Next-generation sequencing (NGS) has limitations in identifying all disease-causing genomic variations in Mendelian diseases.
• Approximately one-third of inherited retinal degeneration (IRD) cases remain genetically unsolved, despite identifying nearly 300 disease-associated genes.
• Noncoding mutations are increasingly recognized as significant contributors to disease burden.

Purpose of the Study:

• To systematically investigate the role of noncoding genomic regions in causing IRDs.
• To explore the hypothesis that noncoding mutations in the RPGRIP1 gene contribute significantly to IRD pathogenicity.
• To identify novel genetic variants underlying unsolved IRD cases.

Main Methods:

• Focused on the RPGRIP1 gene, known to be associated with various IRD phenotypes like Leber congenital amaurosis (LCA).
• Performed whole-genome sequencing (WGS) on 25 patients with unassigned IRD carrying a single RPGRIP1 mutation.
• Validated identified noncoding variants using direct sequencing and in vitro assays.

Main Results:

• Identified three noncoding variants in RPGRIP1 as potential second hits in three LCA patients.
• These variants include a 2,890 bp deletion and two deep-intronic variants (c.2710+233G>A and c.1468-263G>C).
• Validated the pathogenicity of these identified mutant alleles.

Conclusions:

• Noncoding pathogenic variants play a significant role in the genetic etiology of unsolved IRD cases.
• This study expands the understanding of genetic causes for IRDs beyond coding regions.
• Highlights the importance of exploring noncoding DNA for diagnosing rare genetic disorders.