Abstract
Purpose: :
To assess the % penetrance in carrier females in pedigrees with Congenital idiopathic Nystagmus (CIN) caused by FRMD7 gene mutations.
Methods: :
By reviewing all the published work on FRMD7 mutations in CIN it has been possible to calculate the percentage penetrance in carrier females for the 20 published pedigrees with FRMD7 mutations. For each pedigree, the % penetrance in carrier females has been calculated and families grouped into those which have a predicted truncating FRMD7 mutation and those which have a predicted non-truncating mutation.The difference in penetrance rates for the two groups has been tested for significance using both a logistic regression model and a random effects model.
Results: :
Our results show that the average penetrance rate for truncating mutations is 31.9% and for predicted non-truncating mutations is 64.0%. Therefore, the penetrance in carrier females is significantly lower than for non-truncating mutations. Using a logistic regression model, the estimated odds ratio of penetrance with a non-truncating mutation rather than a truncating mutation is 4.8 (95% confidence interval 2.3 to 10.2, p<0.001). Similarly, using a random effects model to adjust for the difference in carrier numbers between pedigrees, a revised estimate of 5.2 (95% confidence interval 1.5 to 17.9, p=0.009) is predicted. Therefore, a statistically significant difference in penetrance exists between truncating and non-truncating mutations although it is important to note that most of the data regarding the outcome of a particular mutation is derived purely from in silico predictions and therefore the strength of this correlation may be underestimated here.
Conclusions: :
In X-linked CIN pedigrees, penetrance among female obligate carriers is known to vary and values have ranged from 30 to 100%. Reasons for this have been suggested and include; skewed X-inactivation, interactions with other genes, and other non-genetic developmental influences on oculomotor development. Indeed, a high rate of X-inactivation skewing with a complex pattern in a CIN pedigree with a truncating FRMD7 mutation has been previously reported by us. Perhaps, the difference in penetrance between truncating and non-truncating mutations provides an insight into the contribution of nonsense-mediated mRNA decay (NMD), haploinsufficiency, cell selection and X-inactivation on the nystagmus phenotype. In our poster, we propose 2 possible explanations for this observation.
Keywords: nystagmus • genetics