An USH2A founder mutation is the cause of Usher syndrome type 2 in Sardinia

Introduction: Usher syndrome (USH) is the most common cause of combined sight and hearing loss, responsible for half of deaf-blindness cases. USH has divided into three types: USH1, characterized by severe bilateral hearing loss and early retinitis pigmentosa (RP); USH2, distinguished by moderate hearing loss and RP; USH3, showing progressive hearing loss, vestibular dysfunction and RP. USH is associated with 19 loci, with 16 causative genes identified. Here, we describe the clinical findings and molecular analysis of 3 USH-affected unrelated families living in the island of Sardinia (Italy). Materials and Methods: We investigated all the members of 3 families in which 9 patients showed both sensorineural hearing loss and RP. All individuals underwent a complete ophthalmic examination and vestibular medical tests. Whole-genome sequencing data were available for genetic analysis. Results: Clinical hypothesis indicated a suspected USH2 syndrome. We identified a single missense causal variant in the USH2A gene, in homozygous status in all patients and heterozygous in unaffected parents. Mutation-related haplotype reconstruction revealed a founder effect. To understand if this event was restricted to a geographical area or whole island, we analysed about 3500 Sardinians, revealing a frequency of about 2% heterozygotes distributed overall in Sardinia. Conclusions: By using our approach, we were able to describe the first case of USH syndrome, its incidence and distribution in Sardinia. Thus, we are able to provide an attractive perspective for the feasibility of carrier status screening, possible genetic counselling at the base for prevention and early treatment strategies of this hereditary syndrome.