20.500.12556/RUL-133089 Clinical and haplotypic variability of Slovenian USH2A patients homozygous for the c. 11864G>A nonsense mutation Purpose: to determine a detailed clinical and haplotypic variability of the Slovenian USH2A patients with homozygous c.11864G>A (p.Trp3955Ter) nonsense mutation and to develop sensitive, accurate and rapid screening test. Methods: Ten unrelated homozygous patients with detailed ophthalmological exam were included in our study. The High-Resolution Melting (HRM) method was developed for fast and reliable detection of the c.11864G>A mutation. Results: The c.11864G>A mutation represents the vast majority of pathogenic alleles in Slovenian USH2A-Usher syndrome population (84%). The median age of onset of nyctalopia was 16 years and all patients younger than 40 years had hyperautofluorescent rings on fundus autofluorescence imaging. The Kaplan Meier survival analysis showed a decline of central vision after the age of 40, with 50% patients reaching visual acuity (VA) ≤ 0.05 at the average age of 66 years visual field diameter less than 20° at the average age of 59 years. There was a relatively large phenotypic variability in the retinal and audiological phenotype. Analysis of the p.Trp3955Ter-homozygous patients revealed four different haplotypes, with the frequency of the most common haplotype ~65%. Disease severity did not correlate with the haplotype. Conclusions: According to the natural history of homozygous p.Trp3955Ter patients any therapy aimed to slow disease progression in these patients would be best started before the age of 40. Phenotypic variability suggests the presence of cis and/or trans factors outside the USH2A gene that are able to affect disease severity. High frequency of p.Trp3955Ter mutation in Slovenian USH2A gene pool appears to be initiated from different unrelated founders because of migrations from neighboring populations. The mutation on haplotype 2 seems to be the major founder allele. USH2A haplotypic variability homozygous mutation usher syndrome founder effect haplotype analysis high resolution melting analysis USH2A haplotipska spremenljivost homozigotna mutacija true false true Angleški jezik Slovenski jezik Članek v reviji 2021-11-11 08:45:36 2021-11-11 08:45:41 2022-09-12 04:14:48 0000-00-00 00:00:00 2019 0 0 12 str. iss. 12, art. 1015 Vol. 10 2019 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 617.7 2073-4425 10.3390/genes10121015 34616281 RAZ_Zupan_Andrej_2019.pdf RAZ_Zupan_Andrej_2019.pdf 1 2D26D49EDA5E9A631D06B17562089C42 e783c3b87d64714ae804b2684924f201172396103e3bb3ba7f221dee56a0ebff 92703d51-42c3-11ec-abdb-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=150878 https://www.mdpi.com/2073-4425/10/12/1015 1 4fe5a7d2-42c3-11ec-abdb-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=150877 Medicinska fakulteta 0 0 0