Natural history of Usher type 2 with the c.2299delG mutation of USH2A in a large cohort

ABSTRACT

Background

The c.2299delG mutation is prevalent and accounts for 24.5% USH2A pathogenic variants, with promising prospects for customized gene therapy.

Materials and Methods

We compared the ocular and auditory phenotypes in a retrospective cohort of 169 Usher type 2 patients, with and without the c.2299delG allele, including visual acuity, slit-lamp examination, optical coherence tomography, kinetic perimetry, and audiometric assessment to define the hearing disability. Statistical methods used were covariate balancing propensity score and adjusted survival curves log-rank test for the analysis of visual acuity.

Results

We compare 54 Usher patients (31%) carrying at least one c.2299delG allele to 109 patients without this variant. The mean ages at onset of night blindness (14 years) and onset of peripheral vision deficiency (24 years) were similar in both groups, as was the severity of hearing loss (p = 0.731), even in homozygotes (p = 0.136). Based on the covariate balancing propensity score, the c.2299delG carrier patients developed cataract and reached a BCVA of 20/63 earlier than patients without this mutation (mean age 36 versus 42 y.o.; and 52.2 versus 55.1 y.o., respectively). Using adjusted survival curves and a log-rank test based on inverse probability weighting, patients with the c.2299delG variant reach blindness (BCVA <20/400) at 42.3 years old instead of 79.8 years for other USH2A pathogenic variants.

Conclusions

We conclude that c.2299delG is associated with a more severe phenotype of the Usher type 2, in homozygotes and in compound heterozygotes.

KEYWORDS:

• Usher
• retinitis pigmentosa
• c.2299delG
• USH2A
• propensity score

Acknowledgments

The authors would like to acknowledge Professor Christian Hamel for his trust and support. He initiated the study. The authors also thank Professor François Willermain for scientific support, and Catherine Dehon and Judith Racapé for their initial support with statistical methods.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Institutional review board statement

The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board of Montpellier University Hospital. The Ministry of Public Health accorded approval for biomedical research under the authorization number 11018S.

Informed consent statement

Informed consent was obtained from all subjects involved in the study according to the Declaration of Helsinki.

Data availability statement

The data presented in this study are available on request from the corresponding author. The data are not publicly available due to private medical and genetic information about patients [email protected]

Supplementary Materials

Supplemental data for this article can be accessed on the publisher’s website.

Additional information

Funding

This research received no grants but awards from Foundation Vesale, no grant number known, no APC known, and Foundation Saucez Van-Pouck, no grant number known, no APC known.