Research Article: Unravelling the pathogenic role and genotype-phenotype correlation of the USH2A p.(Cys759Phe) variant among Spanish families

Date Published: June 18, 2018

Publisher: Public Library of Science

Author(s): Raquel Pérez-Carro, Fiona Blanco-Kelly, Lilián Galbis-Martínez, Gema García-García, Elena Aller, Blanca García-Sandoval, Pablo Mínguez, Marta Corton, Ignacio Mahíllo-Fernández, Inmaculada Martín-Mérida, Almudena Avila-Fernández, José M. Millán, Carmen Ayuso, Dror Sharon.


Mutations in USH2A cause both isolated Retinitis Pigmentosa (RP) and Usher syndrome (that implies RP and hearing impairment). One of the most frequent variants identified in this gene and among these patients is the p.(Cys759Phe) change. However, the pathogenic role of this allele has been questioned since it was found in homozygosity in two healthy siblings of a Spanish family. To assess the causative role of USH2A p.(Cys759Phe) in autosomal recessive RP (ARRP) and Usher syndrome type II (USH2) and to establish possible genotype-phenotype correlations associated with p.(Cys759Phe), we performed a comprehensive genetic and clinical study in patients suffering from any of the two above-mentioned diseases and carrying at least one p.(Cys759Phe) allele.

Diagnosis was set according to previously reported protocols. Genetic analyses were performed by using classical molecular and Next-Generation Sequencing approaches. Probands of 57 unrelated families were molecularly studied and 63 patients belonging to these families were phenotypically evaluated.

Molecular analysis characterized 100% of the cases, identifying: 11 homozygous patients for USH2A p.(Cys759Phe), 42 compound heterozygous patients (12 of them with another missense USH2A pathogenic variant and 30 with a truncating USH2A variant), and 4 patients carrying the p.(Cys759Phe) allele and a pathogenic variant in another RP gene (PROM1, CNGB1 or RP1). No additional causative variants were identified in symptomatic homozygous patients. Statistical analysis of clinical differences between zygosity states yielded differences (p≤0.05) in age at diagnosis of RP and hypoacusis, and progression of visual field loss. Homozygosity of p.(Cys759Phe) and compound heterozygosity with another USH2A missense variant is associated with ARRP or ARRP plus late onset hypoacusis (OR = 20.62, CI = 95%, p = 0.041).

The present study supports the role of USH2A p.(Cys759Phe) in ARRP and USH2 pathogenesis, and demonstrates the clinical differences between different zygosity states. Phenotype-genotype correlations may guide the genetic characterization based upon specific clinical signs and may advise on the clinical management and prognosis based upon a specific genotype.

Partial Text

Retinitis Pigmentosa (RP; MIM#268000) is the most common form of Inherited Retinal Dystrophies (IRD),with a prevalence of approximately 1 in 4000 [1]. It is characterized by primary degeneration of the rods in the early stage of the disease, with progressive evolution and, currently, without a treatment, leading to visual impairment or blindness [2]. Night blindness is the first symptom, followed by constriction of the peripheral visual field, and slow and progressive decrease of central vision [3]. RP is highly heterogeneous, both clinically and genetically. RP can be a non-syndromic disease which represents 70–80% of RP cases or it can be associated with other systemic alterations (syndromic RP; 20–30%) [4]. Usher syndrome (USH), the most frequent IRD syndromic disorder, is defined by sensorineural hearing loss together with RP. The three clinical subtypes: Usher syndrome type I (USH1) (MIM#276901), type II (USH2) (MIM#276902) and type III (USH3) (MIM#276903) are distinguished depending on the severity and onset of visual impairment and hearing loss, and on the presence of vestibular impairment [5].

In this work, we have analyzed by different molecular approaches a large cohort of non-syndromic ARRP and USH2 patients. All the fifty-seven probands studied were characterized, 53 of them presenting the p.(Cys759Phe) variant both in homozygous or compound heterozygous state. Even though in the literature this variant has been reported in over 90 RP patients and 40 USH2 patients [6,11–14,21,25,27,41–47], Gonzalez-del Pozo et al have questioned the pathogenic role of this variant, at least when it appears homozygously [17]. Herein we report a total of 11 homozygous families (14 patients) for the p.(Cys759Phe) variant (S1 Fig). In these families, any other candidate variants in the USH2A gene or other RP genes that could explain the RP or USH2 phenotype were not found by our NGS analysis. Nevertheless, variants in deep-intronic or regulatory regions and complex rearrangements cannot be discarded.




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