Clinical and haplotypic variability of Slovenian USH2A patients homozygous for the c. 11864G>A nonsense mutation

Zupan, Andrej (author), Fakin, Ana (author), Battelino, Saba (author), Jarc-Vidmar, Martina (author), Hawlina, Marko (author), Bonnet, Crystel (author), Petit, Christine (author), Glavač, Damjan (author)

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.

• Language: English
• Keywords: USH2A, haplotypic variability, homozygous mutation, usher syndrome, founder effect, haplotype analysis, high resolution melting analysis
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: MF - Faculty of Medicine
• Publication status: Published
• Publication version: Version of Record
• Year: 2019
• Number of pages: 12 str.
• Numbering: Vol. 10, iss. 12, art. 1015
• PID: 20.500.12556/RUL-133089
• UDC: 617.7
• ISSN on article: 2073-4425
• DOI: 10.3390/genes10121015
• COBISS.SI-ID: 34616281
• Publication date in RUL: 11.11.2021

Record is a part of a journal

• Title: Genes
• Shortened title: Genes
• Publisher: Multidisciplinary Digital Publishing Institute (MDPI)
• ISSN: 2073-4425
• COBISS.SI-ID: 523100185

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.
• Licensing start date: 05.12.2019

Secondary language

• Language: Slovenian
• Keywords: USH2A, haplotipska spremenljivost, homozigotna mutacija

Projects

• Funder: ARRS - Slovenian Research Agency
• Project number: P3-0054
• Name: Patologija in molekularna genetika

• Funder: ARRS - Slovenian Research Agency
• Project number: P3-0333
• Name: Očesne bolezni odraslih in otrok