Inherited retinal diseases (IRDs), defined by dysfunction or progressive loss of photoreceptors, are disorders characterized by elevated heterogeneity, both at the clinical and genetic levels. Our main goal was to address the genetic landscape of IRD in the largest cohort of Spanish patients reported to date. A retrospective hospital-based cross-sectional study was carried out on 6089 IRD affected individuals (from 4403 unrelated families), referred for genetic testing from all the Spanish autonomous communities. Clinical, demographic and familiar data were collected from each patient, including family pedigree, age of appearance of visual symptoms, presence of any systemic findings and geographical origin. Genetic studies were performed to the 3951 families with available DNA using different molecular techniques. Overall, 53.2% (2100/3951) of the studied families were genetically characterized, and 1549 different likely causative variants in 142 genes were identified. The most common phenotype encountered is retinitis pigmentosa (RP) (55.6% of families, 2447/4403). The most recurrently mutated genes were PRPH2, ABCA4 and RS1 in autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL) NON-RP cases, respectively; RHO, USH2A and RPGR in AD, AR and XL for non-syndromic RP; and USH2A and MYO7A in syndromic IRD. Pathogenic variants c.3386G > T (p.Arg1129Leu) in ABCA4 and c.2276G > T (p.Cys759Phe) in USH2A were the most frequent variants identified. Our study provides the general landscape for IRD in Spain, reporting the largest cohort ever presented. Our results have important implications for genetic diagnosis, counselling and new therapeutic strategies to both the Spanish population and other related populations.

Background Research focusing on the role of APOE in Parkinson’s disease (PD) has been largely inconclusive, creating a broad discrepancy in association studies. Objective To elucidate the role of APOE alleles in PD risk by studying a large sample size and controlling for population substructure. Patients and Methods In total, 3465 case and control samples were genotyped, obtained from the NINDS Neurogenetics repository. Results No significant differences in ε4 dosages exist between PD cases and controls. The frequency of ε4 carriers differed slightly between cases and controls at 24% (580/2412) and 26% (270/1053), respectively. Likewise, mean dosages of APOE ε2 were not significantly different between cases and controls. APOE ε2 carriers were observed at a frequency of 13.6% (329/2412) among cases and 15% (158/1053) among controls. Logistic regression models evaluating PD as possibly associated with ε4 or ε2 carrier status and allele dosages yielded no significant results. The mean MMSE score among all PD cases was 28.35 (SD = 2.58) and memory loss was reported in only 11.9% (105/879) of cases. Linear regression models comparing MMSE scores as predicted by ε4 or ε2 carrier status and allele dosages were not significant. Conclusions There is no association between APOE epsilon alleles and Parkinson’s disease.

To define genotype-phenotype correlations in the largest cohort study worldwide of patients with biallelic ABCA4 variants, including 434 patients with Stargardt disease (STGD1) and 72 with cone-rod dystrophy (CRD). DESIGN: Cohort study. METHODS: We characterized 506 patients with ABCA4 variants using conventional genetic tools and next-generation sequencing technologies. Medical history and ophthalmologic data were obtained from 372 patients. Genotype-phenotype correlation studies were carried out for the following variables: variant type, age at symptom onset (AO), and clinical phenotype. RESULTS: A total of 228 different pathogenic variants were identified in 506 ABCA4 patients, 50 of which were novel. Genotype-phenotype correlations showed that most of the patients with biallelic truncating variants presented with CRD and that these cases had a significantly earlier AO than patients with STGD1. Three missense variants are associated with CRD for the first time (c.1804C>T; p.[Arg602Trp], c.3056C>T; p.[Thr1019Met], and c.6320G>C; p.[Arg2107Pro]).