CRB1-associated retinopathy: clinical characteristics and molecular genetic features in the Russian population

Purpose: to reveal the phenotype and genotype spectrum in cohort of patients with CRB1-associated retinal degeneration from Russian pathogenic variants. Materials and methods. A prospective cohort study was conducted on 7 patients aged 5 to 38 years from 6 families with CRB1 gene mutations. Clinical examination included best-corrected visual acuity, refraction, Goldmann visual field, slit-lamp biomicroscopy, fundus photography, fundus autofluorescence, and optical coherence tomography. All patients underwent electrophysiological and molecular genetic testing (last-generation sequencing — “Hereditary Retinal Diseases” panel). Results. We revealed 7 different phenotypes of CRB1-associated retinopathies. In all patients compound — heterozygous pathogenic variants in CRB1 genes were found. Among 11 pathogenic variants only three: c.2843G>A, (p.Cys948Tyr), c.2536G>A(p.Gly846Arg21) and c.2308G>A, (p.Gly770Ser) were described on other populations. Pathological sequences in CRB1 gene included 8 previously not described (3 missense: c.1042T>C (p.Cys348Arg), c.2480G>T (p.Gly827Val), c.29T>C (p.Leu10Pro) и 5 nonsense: c.1492delA (p.Ser498Valfs*4), c.2238delT (p.Gln747Asnfs*7), c.624T>G (p.Tyr208*), c.222C>A (p.Cys74*), с.1660del (p.Val554Cysfs*19), which points out the features of Russian population. Missense mutations: c.2308G>A (p.Gly770Ser), c.2480G>T (Gly827Glu) and c.2536G>A (p.Gly846Arg), as well as nonsense mutation c.2238delT (p.Gln747Asnfs*7) are located in “hot” 7 exon of CRB1 gene, in which we also found the biggest number of pathogenic variants. Mutation c.222C>A (p.Cys74*) was found in 3 of 7 patients, 2 of whom were siblings. Conclusions. Cohort of Russian patients with CRB1-associated retinopathy demonstrated wide-spectrum phenotypes of inherited retinal dystrophies, including Leber congenital amaurosis type 8, early onset retinal dystrophy, early onset retinitis pigmentosa (RP) type 12 with or without optic nerve drusen, RP of 12 type with bone spicules and atrophy of the outer layers of parafoveal retina, Coats’ like exudative vasculopathy with cystoid macula oedema, RP with paraarteriolar preservation of retinal pigment epithelium (PPRPE). New molecular genetic characteristics in patients from the Russian population with CRB1-associated inherited retinal dystrophies were revealed.