Clinical and Haplotypic Variability of Slovenian USH2A Patients Homozygous for the c. 11864G&gt;A Nonsense Mutation

Zupan, Andrej; Fakin, Ana; Battelino, Saba; Jarc-Vidmar, Martina; Hawlina, Marko; Bonnet, Crystel; Petit, Christine; Glavač, Damjan

doi:10.3390/genes10121015

Cited by 13 publications

(14 citation statements)

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“…It has identified a total of 421 different sequence variants predicted to be pathogenic, about half of which had not been previously reported [ 43 ]. Although numerous variants in the USH2A gene were reported, as much as 84% of the Slovenian patients with Usher syndrome type 2 had the NM_206933.4:c.11864G>A (p.Trp3955Ter) variant [ 44 ]. As blindness due to the retinitis pigmentosa does not occur during infancy but typically at the age of 10 years for Usher type 1, diagnosing Usher syndrome presents its own set of unique challenges.…”

Section: Genetic Etiology Of Hearing Lossmentioning

confidence: 99%

The Importance of Early Genetic Diagnostics of Hearing Loss in Children

et al. 2020

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Hearing loss is one of the most common sensory deficits. It carries severe medical and social consequences, and therefore, universal newborn hearing screening was introduced at the beginning of this century. Affected patients can have hearing loss as a solitary deficit (non-syndromic hearing loss) or have other organs affected as well (syndromic hearing loss). In around 60% of cases, congenital hearing loss has a genetic etiology, where disease-causing variants can change any component of the hearing pathway. Genetic testing is usually performed by sequencing. Sanger sequencing enables analysis of the limited number of genes strictly preselected according to the clinical presentation and the prevalence among the hearing loss patients. In contrast, next-generation sequencing allows broad analysis of the numerous genes related to hearing loss, exome, or the whole genome. Identification of the genetic etiology is possible, and it makes the foundation for the genetic counselling in the family. Furthermore, it enables the identification of the comorbidities that may need a referral for specialty care, allows early treatment, helps with identification of candidates for cochlear implant, appropriate aversive/protective management, and is the foundation for the development of novel therapeutic options.

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Section: Genetic Etiology Of Hearing Lossmentioning

confidence: 99%

The Importance of Early Genetic Diagnostics of Hearing Loss in Children

et al. 2020

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“…Such complexity makes it near-impossible for a diagnosis to be achieved in most instances solely on the basis of disease phenotype [ 2 , 21 , 22 , 23 ]. Furthermore, even a single pathogenic variant can manifest with phenotypic variability [ 24 ]. For some IRDs, modifier loci have been identified, somewhat blurring the borders between Mendelian and polygenic forms of IRD and mirroring similar observations with other disease aetiologies [ 25 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

Next-Generation Sequencing Applications for Inherited Retinal Diseases

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et al. 2021

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Inherited retinal diseases (IRDs) represent a collection of phenotypically and genetically diverse conditions. IRDs phenotype(s) can be isolated to the eye or can involve multiple tissues. These conditions are associated with diverse forms of inheritance, and variants within the same gene often can be associated with multiple distinct phenotypes. Such aspects of the IRDs highlight the difficulty met when establishing a genetic diagnosis in patients. Here we provide an overview of cutting-edge next-generation sequencing techniques and strategies currently in use to maximise the effectivity of IRD gene screening. These techniques have helped researchers globally to find elusive causes of IRDs, including copy number variants, structural variants, new IRD genes and deep intronic variants, among others. Resolving a genetic diagnosis with thorough testing enables a more accurate diagnosis and more informed prognosis and should also provide information on inheritance patterns which may be of particular interest to patients of a child-bearing age. Given that IRDs are heritable conditions, genetic counselling may be offered to help inform family planning, carrier testing and prenatal screening. Additionally, a verified genetic diagnosis may enable access to appropriate clinical trials or approved medications that may be available for the condition.

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“…USH2A variants have been described to cause most commonly syndromic and non-syndromic forms of recessive IRD in different populations of world. High frequencies of USH2A variants have been reported in USH2 families of Jewish, Spanish, American, Scandinavian, Slovenian, and Italian, British origins [22][23][24][25][26][27][28]. In addition, USH2A variants have been identified to cause a substantial number of non-syndromic RP in families of Caucasian, Japanese, American and Chinese origins [13,25,[29][30][31][32][33].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, USH2A variants have been identified to cause a substantial number of non-syndromic RP in families of Caucasian, Japanese, American and Chinese origins [13,25,[29][30][31][32][33]. Importantly, USH2A variants display a wide phenotypic spectrum, therefore, phenotype-genotype correlation for the most prevalent USH2A variants may facilitate genetic counselling and improve the prognosis of affected individuals, as well as guide for patient-specific treatment options [26].…”

Section: Discussionmentioning

confidence: 99%

“…Available evidences suggest presence of USH2A recurrent variants in different populations as a result of founder effect. Of the 896 previously identified and previously reported USH2A variants in the Human Gene Mutation Database (HGMD), the p.Cys759Phe have been described the most prevalent pathogenic variant in the Spanish population and accounts for 4.5 % of the RP [34,35] and 8.1 % of the USH2 cases [36], Similarly, a USH2A variant p.Trp3955Terwas detected in majority of Slovenian USH2 cases [26]. A deleterious USH2A variant p.Glu767fs have been found associated most commonly with USH2 [24,37] and significantly with nonsyndromic RP Caucasian patients [38].…”

Section: Discussionmentioning

confidence: 99%

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USH2A gene variants cause Keratoconus and Usher syndrome phenotypes in Pakistani families

et al. 2021

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Background 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 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. Methods We 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. Results Disease 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. Conclusions This 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.

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Clinical and Haplotypic Variability of Slovenian USH2A Patients Homozygous for the c. 11864G>A Nonsense Mutation

Cited by 13 publications

References 38 publications

The Importance of Early Genetic Diagnostics of Hearing Loss in Children

The Importance of Early Genetic Diagnostics of Hearing Loss in Children

Next-Generation Sequencing Applications for Inherited Retinal Diseases

USH2A gene variants cause Keratoconus and Usher syndrome phenotypes in Pakistani families

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