Agnes Kriszt1, Gergely Losonczy, András Berta, György Vereb, Lili Takács. 1. Department of Ophthalmology, University of Debrecen Medical and Health Science Center, Debrecen, Hungary; Department of Biophysics and Cell Biology, University of Debrecen Medical and Health Science Center, Debrecen, Hungary.
Abstract
PURPOSE: Complex segregation analysis of 60 unrelated sporadic keratoconus (KC) families was performed to reveal the presumed mode of inheritance in our dataset. METHODS: Sixty probands, 212 family members and 212 age and gender matched healthy controls underwent clinical and videokeratographic examination. Family aggregation and distribution of videokeratography parameters were examined. Segregation of KSI, KISA and 6mm Fourier asymmetry alone or in covariate analysis with gender or the presence of Fleischer ring, exploring mendelian and non-mendelian models of inheritance was tested using complex segregation analysis with the S.A.G.E. program package. RESULTS: In 145 relatives of probands, the estimated prevalence of manifest KC was 7.6% (95% CI: 3.3-11.9) based on KISA index, indicating strong familial aggregation. All examined videokeratography indices were able to differentiate between KC and non-KC family members as well as normal controls (anova p < 0.001). Hypotheses accepted as most parsimonius models of inheritance (p > 0.1) for all indices indicated the presence of a non-mendelian major gene effect (MG). Inclusion of Fleischer ring as covariate improved the fit of MG models. Mendelian, Sporadic and polygenic models were consistently rejected. CONCLUSIONS: Complex segregation analysis indicates a strong genetic contribution to the transmission of keratoconus. Inheritance is most probably due to a non-mendelian major gene effect. Low genotype-phenotype correlation in sporadic KC families can make linkage studies difficult, thus genome wide association studies, epigenetic and pathway analyses may provide more information on disease pathogenesis in non-familial keratoconus.
PURPOSE: Complex segregation analysis of 60 unrelated sporadic keratoconus (KC) families was performed to reveal the presumed mode of inheritance in our dataset. METHODS: Sixty probands, 212 family members and 212 age and gender matched healthy controls underwent clinical and videokeratographic examination. Family aggregation and distribution of videokeratography parameters were examined. Segregation of KSI, KISA and 6mm Fourier asymmetry alone or in covariate analysis with gender or the presence of Fleischer ring, exploring mendelian and non-mendelian models of inheritance was tested using complex segregation analysis with the S.A.G.E. program package. RESULTS: In 145 relatives of probands, the estimated prevalence of manifest KC was 7.6% (95% CI: 3.3-11.9) based on KISA index, indicating strong familial aggregation. All examined videokeratography indices were able to differentiate between KC and non-KC family members as well as normal controls (anova p < 0.001). Hypotheses accepted as most parsimonius models of inheritance (p > 0.1) for all indices indicated the presence of a non-mendelian major gene effect (MG). Inclusion of Fleischer ring as covariate improved the fit of MG models. Mendelian, Sporadic and polygenic models were consistently rejected. CONCLUSIONS: Complex segregation analysis indicates a strong genetic contribution to the transmission of keratoconus. Inheritance is most probably due to a non-mendelian major gene effect. Low genotype-phenotype correlation in sporadic KC families can make linkage studies difficult, thus genome wide association studies, epigenetic and pathway analyses may provide more information on disease pathogenesis in non-familial keratoconus.
Authors: Erik Fransen; Hanne Valgaeren; Katleen Janssens; Manou Sommen; Raphael De Ridder; Geert Vandeweyer; Luigi Bisceglia; Vincent Soler; Alexander Hoischen; Geert Mortier; François Malecaze; Carina Koppen; Guy Van Camp Journal: Eur J Hum Genet Date: 2021-03-19 Impact factor: 4.246
Authors: Vishal Shinde; Nara Sobreira; Elizabeth S Wohler; George Maiti; Nan Hu; Giuliana Silvestri; Sonia George; Jonathan Jackson; Aravinda Chakravarti; Colin E Willoughby; Shukti Chakravarti Journal: Hum Mol Genet Date: 2021-05-17 Impact factor: 6.150