The RePER database, as of November 25, 2022, encompassed 1070 patients clinically diagnosed with a RED (Supplemental Material). Prior to the collaboration between ONERO and RePER in July 2019, 329 patients were already registered, whereas thereafter, 738 patients were added. Following meticulous data scrutiny, 203 patients were excluded due to insufficient data for analysis. Of the latter, 132 patients were registered before the collaborative agreement (constituting 40.1% of patients registered up to that point), while 71 patients were registered afterward (constituting 9.6% of patients registered after the agreement).

Subsequently, a total of 864 patients with RED, comprising 434 females and 430 males with a mean age of 47.1 ± 18.4 years (range: 3-84), were included in the study. The geographic distribution of included patients is illustrated in Fig. 1. RED were categorized as depicted in Fig. 2.

Fig. 1

Geographic location of patients included. The color range indicates the percentage (with darker colors representing higher percentages) of the number subjects included (S) as a proportion of the population (P) in each Spanish Autonomous Community, including the two Autonomous Cities of Ceuta and Melilla. Population data was obtained from the Spanish National Statistics Institute (INE), as of January 1, 2021

Fig. 2

Classification of rare eye diseases and the number of patients included. The number of subjects with a syndromic disease with possible eye involvement but without ocular affectation is indicated as a negative number between brackets

Symptoms and age at onset and at diagnosis

The mean age of symptoms onset, age at first clinical visit and age at diagnosis were 17.1±15.7, 20.1±16.5, and 24.3±16.9 years old respectively. There was no delay between the onset of symptoms and the first visit, except in the IRD subgroup (3.3±7.3 years), the muscular diseases subgroup (4.9±10.9 years) and the delay was less significative in the metabolic diseases (0.2±0,4 years).

Regarding the mean diagnosis delay, it was 2.1±10.3 years in anterior segment diseases, 4.7±12.1 years in congenital malformations, 0.5±1.0 years in inflammatory diseases, 8.0±11.5 years in IRD, 2.1±1.6 years in metabolic diseases, 7.8±11.2 years in muscular diseases, 2.7±7.8 years in the neurological diseases group, and there was no delay in tumor diseases. The most prevalent symptoms are shown in Table 1.

Table 1 The most prevalent symptoms were reported in the total sample and at each disease groupOther diseases and ocular surgeries

Five hundred and forty-five patients (63.1%) reported suffering from other eye diseases in addition to the reported RED. The most prevalent ones are detailed in Table 2. Two hundred and eighty-six patients (33.1%) reported undergoing ocular surgeries, with the most common procedures outlined in Table 3. Additionally, 408 patients (47.2%) reported having a systemic disease, with the most prevalent ones categorized and presented in Table 4.

Table 2 The most prevalent secondary eye diseases/features in the total sample and each disease groupTable 3 The most common ocular surgeries in the total sample and each disease groupTable 4 The most prevalent systemic diseases/features in the total sample and each disease groupCertificates of disability, incapacity for work, and dependence

Seven hundred and forty-eight (86.6%) possessed a certificate of disability, with a mean disability degree of 77.4±8.8%. Among these, 44 patients from the anterior segment disease group had a degree of 76.6±10.2%, 22 from the congenital malformation group had 66.8±19.6%, 3 patients with inflammatory diseases had 79.7±6.8%, 602 patients with IRD had 74.8±12.9%, 10 patients with a metabolic disease had 63.7±16.7%, 37 patients with a muscular disease exhibited 63.2±17.3%, 28 patients with neurological diseases had 78.4±7.4%, and 2 patients affected by tumors had a degree of disability of 51.0±25.5%.

According to Spanish and European laws, 359 patients (41.6%) were recognized as having incapacity for work: 3 patients (0.8%) had temporary incapacity, 24 patients (6.7%) had total permanent incapacity, 203 patients (56.4%) had absolute permanent incapacity, and 129 patients (36.0%) had severe disability. The types of incapacity for work for each group are detailed in Fig. 3.

Fig. 3

Distributions of type of incapacity for work (top, left), level of dependence degree (top, right), visual impairment and blindness (bottom, left), and inheritance pattern (bottom, right) per disease group. The number in the bars indicate the number of subjects

One hundred and sixty-six patients (19.2%) had some degree of recognized dependence, categorized as moderate for 77 patients (46.4%), severe for 49 patients (29.5%), and great dependence for 40 patients (24.1%). The levels of dependence degree for each subgroup are illustrated in Fig. 3.

Visual acuity and visual field

VA data were available for 719 patients (83.2%). Of these, 243 patients (33.8%) had no visual impairment, 95 (13.2%) had mild impairment, 130 (18.1%) had moderate impairment, 58 (8.1%) had severe impairment, and 193 (26.8%) were blind. The classification per disease group is depicted in Fig. 3.

VF results were obtained for 465 patients (53.8%). Among these, 19 had no VF defects. Seventy-one patients (8.2%) presented a VF with central and/or paracentral scotoma (58 belonged to the IRD group, 12 to the neurological group and 1 to the inflammatory group). Two-hundred and seventy-four patients (31.7%) had a concentric contraction of the VF, all of them belonging to the IRD group (39 subjects had a mild contraction, 89 a moderate contraction and 146 a severe contraction). Seventy patients (8.1%) had abolished VF (63 belonged to the IRD group, 6 to the neurological group, and 1 to the anterior segment group). Thirty-one patients (3.6%) presented other defects of VF (23 belonged to the IRD group, 5 to the neurological group, 2 to the anterior segment group, and 1 to congenital malformations group).

Family members affected and genetic diagnosis

Three-hundred and ninety-one patients (45.3%) reported to have at least one family member diagnosed with the same disease. The most frequently affected family members were siblings (260, 30.0%), followed by mother (75, 8.7%), father (54, 6.2%), maternal cousins (49, 5.7%), sons/daughters (47, 5.4%), maternal uncles/aunts (41, 4.7%), paternal cousins (27, 3.1%), paternal uncles/aunts (25, 2.9%), maternal grandfather (22, 2.5%), maternal grandmother (19, 2.2%), paternal grandfather (11, 1.3%) and paternal grandmother (8, 0.9%).

Six hundred and fifty-six patients (75.9%) had a genetic report. Among these, 461 (70.3%) had a positive genetic result, 47 (7.2%) had an inconclusive result, 36 (5.5%) had an uncertain result, 106 (16.2%) had a non-informative result, and 6 (0.9%) could not be genetically characterized due to the reports presenting incompatible or incongruent information.

The inherited pattern of patients with a genetic disease was autosomal dominant (138, 29.9%), autosomal recessive (251, 54.5%), X-linked (42, 9.1%), mitochondrial (29, 6.3%), and one patient had a multimendelian phenotype of syndromic RP due to mutations in the USH2A gene with recessive inheritance and the RHO gene which is autosomal dominant. The distribution of inheritance patterns per disease group is depicted in Fig. 3. The genes involved in positive results and the most common mutations, are listed in Tables 5 and 6 respectively. We have identified 62 new pathogenic or likely pathogenic variants that have not been previously reported in genetic variant databases associated with specific phenotypes. However, some of these variants are present in the population database Genome Aggregation Database (gnomAD) v4.1.0. In such cases, allele frequencies and their respective reference SNP identification (rsID) numbers are provided in Table 7. Additionally, two variants have been documented in scientific publications: the c.5898G>A variant in ABCA4 (PMID: 25608812), and the c.946G>T variant in Col1A2 (PMID: 30190494).

Table 5 Genes involved in positive genetic resultsTable 6 Mutations most frequently identified in genetic reports.Table 7 New variants not previously published in genetic variant databases associated with specific phenotypes