A Genotype-Phenotype Analysis of Usher Syndrome in Puerto Rico: A Case Series

Introduction Patients with Usher syndrome (USH) have retinitis pigmentosa (RP) and hearing loss inherited as an autosomal recessive (ar) trait. Mutations in the USH2A gene are the most common cause of Usher syndrome. We report the genotype-phenotype correlation in 10 patients with Usher syndrome from Puerto Rico (PR). This is the first genotype-phenotype analysis of patients with the syndrome in PR. Methods We conducted a chart review of patients who carried an Usher syndrome diagnosis. They underwent a comprehensive ophthalmic evaluation by at least one of the authors. This included best corrected visual acuity (BCVA), visual field mean deviation (VF MD), pattern standard deviation (PSD), and macular optical coherence tomography (mOCT) average volume and thickness. Genotyping was done using the Invitae Inherited Retinal Disease (IRD) Panel. Results Three patients had a logMAR BCVA of 1.0 or worse. The median VF MD was -29.7 dB and -29.2 dB in the OD and OS, respectively. The median PSD was 5.5 dB and 5.7 dB in the OD and OS, respectively. Upon macular OCT, patients had a median volume of 8.4 μm³ and 8 μm³ in the OD and OS, respectively. The median thickness was 235 μm and 223 μm in the OD and OS, respectively. All patients had pathogenic USH2A variants, and eight of these were compound heterozygotes. The most common variants were p.Cys575Tyr and p.Glu767Serfs*21, each present in four patients. Patients with the p.Cys759Phe variant had the worst phenotype with the worst BCVA, largest VF MD, and slimmer macular thickness. Conclusion Our findings are compatible with previously reported pathogenic mutations in the USH2A gene. However, the p.Cys759Phe variant has previously been correlated with a mild phenotype. In our study, the p.Cys759Phe variant correlated with the most severe phenotype. This variant has a high prevalence in the Spanish population, and PR was a Spanish colony for 400 years. The presence of this variant could be traced back to Spain. Genotyping patients with Usher syndrome is of utmost importance. Further studies to evaluate the common founder effect of patients with the syndrome in PR are warranted.