Genetic screening of Russian Usher syndrome patients toward selection for gene therapy

ABSTRACT

Background: Usher syndrome (USH) is heterogeneous in nature and requires genetic test for diagnosis and management. Mutations in USH associated genes are reported in some populations except Russians. Here, we first time represented the mutation spectrum of a Russian USH cohort.

Methods: Twenty-eight patients with USH were selected from 3214 patients from Deaf-Blind Support Foundation “Con-nection” during 2014–2016 following the observational study NCT03319524. Complete ophthalmologic, ENT, and vestibular medical tests were done for clinical characterization. NGS, MLPA, and Sanger sequencing were considered for genetic analysis.

Results: Around 53.57% and 39.28% patients had USH1 and USH2, respectively; 17.85% cases (n = 5/28) had no known mutation. Eleven (73.33%) subjects showed variations in USH1 associated genes MYO7A (72.72%), CDH23 (9.09%), PCDH15 (9.09%), and USH1C (9.09%). Eleven mutations are detected in MYO7A where 54.54% are novel. MYO7A: p.Q18* was most frequent (27.27%) mutation and is associated with early manifestation and most severe clinical picture. Two novel mutations (p.E1301* and c.158-?_318+?del) are detected in PCDH15 gene. Around 90.90% patients suspected to be USH2 are confirmed by genetic testing. Eleven mutations detected in the USH2A gene, where 27.27% were novel. Most common USH2A mutation is p.W3955* (50%) followed by p.E767fs, p.R1653*, and c.8682-9A> G (20% each).

Conclusion: The Russian USH cohort shows both novel and known USH mutations. Clinically the prevalence of USH2 is low (39.28%) and the frequency of MYO7A mutations responsible for USH1B is very high (63.63%, N = 7/11) compared to other cohorts. These seven patients carrying MYO7A mutations are preliminarily eligible for the UshStat® gene therapy.

KEYWORDS:

• Usher syndrome
• MYO7A
• USH2A
• gene therapy
• Russian cohort

Acknowledgments

Authors would like to thank personnel of ROO Association of sign language interpreters for accompanying patients. Funding: ANO “Sensor technology for deafblind” and Deaf-Blind Support Foundation “Con-nection”.

Authors contributions

MEI, DSA, and IIN designed the study protocol and did paperwork for ethics committee application. AMD and DMG recruited patients. VNT, OMO, DMG provided ophthalmological examination and diagnosing patients. ASM provided otodiagnostics, KVO provided otoneurologic examination, AFH provided posturometric examination, TVM conducted physical examination, genetic counseling, and genealogy trees graphics. VVS, IVV, DVZ, KIA, and AIK provided NGS sequencing, sample aliquoting and bioinformatic analysis of samples as well as MPLA and Sanger sequencing. AAP provided biobanking of DNA samples under SOP protocol requirements, MEI and AAP registered the study in clinicaltrials.gov. DB and AIK did the bioinformatic analysis, MEI and DB organized all data and reanalysis. MEI, DB, and VVS wrote the manuscript.

Conflict of interest

The authors declare no conflict of interest.

Supplemental data

Supplemental data for this article can be accessed at https://doi.org/10.1080/13816810.2018.1532527.

Additional information

Funding

ANO “Sensor technology for deafblind” and Deaf-Blind Support Foundation Connection.