Predominant Founder Effect among Recurrent Pathogenic Variants for an X-Linked Disorder

Area of Science:

• Genetics
• Ophthalmology
• Molecular Biology

Background:

• X-linked retinoschisis (XLRS) is caused by pathogenic variants in the RS1 gene.
• Recurrent pathogenic variants are frequently observed in unrelated XLRS probands, suggesting potential mutational hotspots or founder effects.

Purpose of the Study:

• To investigate the contribution of mutational hotspots versus founder allele events to recurrent pathogenic variants in the RS1 gene.
• To improve the accuracy of clinical variant classification for X-linked retinoschisis.

Main Methods:

• Analysis of a cohort of 332 unrelated XLRS probands, including variant classification and enrichment analysis.
• Haplotype analysis using microsatellite and single nucleotide polymorphisms on 19 recurrently observed RS1 variants in 190 probands.

Main Results:

• 108 unique RS1 variants were identified in the cohort.
• Haplotype analysis revealed common variant-specific haplotypes in 14 of 19 evaluated variants.
• 25 distinct shared haplotypes were identified in 99 out of 190 probands, indicating a significant role of the founder effect.

Conclusions:

• The founder effect plays a significant role in the recurrence of pathogenic RS1 variants in X-linked retinoschisis.
• This finding enhances the accuracy of clinical variant classification for XLRS and may be applicable to other X-linked disorders.