Abstract
Purpose :
Usher syndrome (USH) is a rare genetic autosomal recessive (AR) disorder characterized by sensorineural hearing loss and retinitis pigmentosa. We performed prospective observational natural history clinical trial to clarify genotype-phenotype correlation of Usher syndrome patients in Russia for possible further treatment application
Methods :
118 syndromic RP patients with hearing loss of AR and sporadic inheritance were included under NCT03901391 and NCT03319524 protocols. Complete ophthalmic and audiology examinations were conducted in all the study subjects. DNA samples were extracted from patients’ peripheral blood for whole exome sequencing (WES) analysis. Sanger sequencing was conducted for validating the identified mutations and cosegregation pattern in the families, MLPA was done for deletions borders clarification.
Results :
USH patient group data is in Table 1. USH1 patients with biallelic mutations in MYO7A (14 cases), USH1C (1 case), CDH23 (2 cases), PCDH15 (2 cases) and CIB2 (1 case). USH2 patients with biallelic mutations in USH2A (71 cases), 15 of them are newly reported mutations in USH2A gene and are provided in Table 2. 7 patients had W3955X USH2A mutation – 3 homozygous and 4 – in compound heterozygous state with another confirmed pathogenic mutation, which are considered to be of founder effect from eastern Europe, one of the patients had deletion of 38 exon of USH2A c.7121-?_7303+? del, mutations in GPR98 (1 case), DFNB31 (2 cases). In 6 patients biallelic CLRN1 gene mutations were confirmed of USH3 group, 3 of those patients have known ancestors from Baltic region including Finland. Partially solved cases included USH2A: 1 heterozygous mutation, no second mutation found (3 cases), POC1B (1 case), EYS (1 case) – two compound heterozygous mutations, PRGR hemizygous mutation – but no genetic causes of hearing loss is found in these cases. GJB2 hearing loss genetically confirmed, but no genetic causes of vision loss found (3 cases). There were USH phenotype patients with confirmed another genetic disease: NIPBL (Cornelia de Lange syndrome 1), LOXHD1 (Deafness, autosomal recessive 77), PRGR (X-linked retinitis pigmentosa), PEX6 (Zellweger spectrum disorder). No any mutations found in 4 USH patients.
Conclusions :
This study clarified main genetic causes of Usher syndrome and its phenocopies in Russian patients, 15 novelvariants in USH2A gene were identified.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.