Abstract
BackgroundRetinitis pigmentosa (RP) is the most common inherited retinal dystrophy, affecting approximately 1 in 4000 individuals worldwide. The most common form of syndromic RP is Usher syndrome (USH) accounting for approximately 20–30 % of RP cases. Mutations in the USH2A gene cause a significant proportion of recessive non-syndromic RP and USH type II (USH2). This study aimed to determine the causative role of the USH2A gene in autosomal recessive inherited ocular diseases and to establish genotype-phenotype correlation associated with USH2A variants.MethodsWe performed direct Sanger sequencing and co-segregation analysis of the USH2A gene to identify disease causing variants in a non-syndromic RP family, two USH2 families and two Keratoconus (KC) families.ResultsDisease causing variants in the USH2A gene were identified in two families displayed KC and USH2 phenotypes. A novel variant c.4029T > G, p.Asn1343Lys in the USH2A gene was detected in a Pakistani family with KC phenotype. In addition, a missense variant (c.7334 C > T, p. Ser2445Phe) in the USH2A gene was found segregating in another Pakistani family with USH2 phenotype. Homozygosity of identified missense USH2A variants was found associated with autosomal recessive inherited KC and USH2 phenotypes in investigated families. These variants were not detected in ethnically matched healthy controls. Moreover, the USH2A variants were predicted to be deleterious or potentially disease causing by PolyPhen-2, PROVEAN and SIFT.ConclusionsThis study provided first evidence for association of a novel USH2A variant with KC phenotype in a Pakistani family as well as established the phenotype-genotype correlation of a USH2A variant (c.7334 C > T, p. Ser2445Phe) with USH2 phenotype in another Pakistani family. The phenotype-genotype correlations established in present study may improve clinical diagnosis of affected individuals for better management and counseling.
Highlights
Retinitis pigmentosa (RP) is the most common inherited retinal dystrophy, affecting approximately 1 in 4000 individuals worldwide
Progression and age of onset of these features Usher syndrome (USH) is divided into three clinical types: USH type 1 (USH1:MIM #276,901), USH type 2 (USH2: MIM#276,902) and USH type 3 (USH3: MIM#276,903), [6]
Clinical characteristics Disease causing variants in the USH2A gene were identified in a four-generation KC family and a twogeneration USH2 family as shown in Fig. 1 (i) and (ii) a.Ophthalmology reports on affected members of both families confirmed clinical diagnosis of KC and USH2
Summary
Retinitis pigmentosa (RP) is the most common inherited retinal dystrophy, affecting approximately 1 in 4000 individuals worldwide. The most common form of syndromic RP is Usher syndrome (USH) accounting for approximately 20–30 % of RP cases. Mutations in the USH2A gene cause a significant proportion of recessive nonsyndromic RP and USH type II (USH2). Inherited retinal dystrophies (IRDs) are a broad group of clinically and genetically heterogeneous rare eye diseases resulting in progressive visual impairment or blindness [1]. Retinitis pigmentosa (RP; MIM#268,000) is the most prevalent form of IRDs, affecting approximately 1 in 4000 individuals worldwide [2]. The most common form of syndromic RP is Usher syndrome (USH) and the general prevalence of USH approximately ranges from 1 to 4 in 25,000 individuals [5]. Each USH subtype is genetically heterogeneous and several genes have been described for all three types
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