Abstract
Purpose :
This study investigates mutations in the X-linked genes FRMD7, RPGR, and RP2, known to cause nystagmus or retinitis pigmentosa. In males, these genetic defects are fully penetrant in comparison, female carriers show variable penetrance. Traditionally, this variability is attributed to random X-chromosome inactivation.
It is unclear whether mutation type influences penetrance. Using a combination of datasets from literature and our local datasets this study aimed to explore the impact of mutation type on penetrance in female carriers.
Methods :
We obtained genotypic and pedigree data for participants with known FRMD7, RPGR and RP2 variants from published datasets (n=165 studies) and our local cohorts. We identified a total of 431 pedigrees that met our inclusion criteria. Female carriers were classified into affected and unaffected status. The average weighted penetrance for both truncating and non-truncating mutations was calculated. We used a logistic regression model to assess for statistical significance of differences in penetrance based on mutation type.
Results :
In families with FRMD7 mutations (n=115), the weighted average penetrance was 41.4%. Truncating mutations showed 29.7% penetrance, while non-truncating mutations had 49.8% (p<0.0001). For pedigrees with RPGR mutations (n=258), the weighted average penetrance was 22.7% with truncating mutations showing 23.8% penetrance, and non-truncating mutations 16.7% (p=0.043). For RP2 mutations (n=58 pedigrees), the overall penetrance was 13.4%, with 14.0% in truncating and 11.9% in non-truncating mutations (p=0.69).
Conclusions :
Our findings indicate a significant difference in penetrance between truncating and non-truncating mutations in FRMD7, with truncating mutations being less penetrant. In RPGR, truncating mutations were slightly more penetrant, but with marginal statistical significance. RP2 mutations showed a similar trend, but the differences were not statistically significant. Skewed X-inactivation could be a possible mechanism for the mutation specific penetrance observed. In addition, we observed a higher proportion of pedigrees with truncating mutations than non-truncating mutations for RPGR and RP2. These insights could be pivotal in genetic counselling and warrant further research studies.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.