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Article

Clinical and Haplotypic Variability of Slovenian USH2A Patients Homozygous for the c. 11864G>A Nonsense Mutation

1
Department of Molecular Genetics, Institute of Pathology, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
2
Eye Hospital, University Medical Centre Ljubljana, Grablovičeva 46, 1000 Ljubljana, Slovenia
3
Department of Otorhinolaryngology and Cervicofacial Surgery, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia
4
Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
5
Unité de Génétique et Physiologie de l’Audition, Institut Pasteur, 75015 Paris, France
6
Unité Mixte de Recherche en Santé (UMRS) 1120, Institut National de la Santé et de la Recherche Médicale (INSERM), 75015 Paris, France
7
Complexité du Vivant, Sorbonne Universités, Université Pierre et Marie Curie, Université Paris 06, 75005 Paris, France
8
Institut de l’Audition, 75012 Paris, France
9
Syndrome de Usher et Autres Atteintes Rétino-Cochléaires, Institut de la Vision, 75012 Paris, France
10
Collège de France, 75005 Paris, France
*
Authors to whom correspondence should be addressed.
The authors contributed equally to this work.
Genes 2019, 10(12), 1015; https://doi.org/10.3390/genes10121015
Received: 31 October 2019 / Revised: 25 November 2019 / Accepted: 3 December 2019 / Published: 5 December 2019
(This article belongs to the Special Issue Recent Advances in Inherited Eye Disease)
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. View Full-Text
Keywords: usher syndrome; founder effect; haplotype analysis; high resolution melting analysis usher syndrome; founder effect; haplotype analysis; high resolution melting analysis
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MDPI and ACS Style

Zupan, A.; Fakin, A.; Battelino, S.; Jarc-Vidmar, M.; Hawlina, M.; Bonnet, C.; Petit, C.; Glavač, D. Clinical and Haplotypic Variability of Slovenian USH2A Patients Homozygous for the c. 11864G>A Nonsense Mutation. Genes 2019, 10, 1015. https://doi.org/10.3390/genes10121015

AMA Style

Zupan A, Fakin A, Battelino S, Jarc-Vidmar M, Hawlina M, Bonnet C, Petit C, Glavač D. Clinical and Haplotypic Variability of Slovenian USH2A Patients Homozygous for the c. 11864G>A Nonsense Mutation. Genes. 2019; 10(12):1015. https://doi.org/10.3390/genes10121015

Chicago/Turabian Style

Zupan, Andrej; Fakin, Ana; Battelino, Saba; Jarc-Vidmar, Martina; Hawlina, Marko; Bonnet, Crystel; Petit, Christine; Glavač, Damjan. 2019. "Clinical and Haplotypic Variability of Slovenian USH2A Patients Homozygous for the c. 11864G>A Nonsense Mutation" Genes 10, no. 12: 1015. https://doi.org/10.3390/genes10121015

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