Relative frequency of inherited retinal dystrophies in Brazil

www.nature.com/scientificreports OPEN Relative frequency of inherited retinal dystrophies in Brazil Fabiana Louise Motta1, Renan Paulo Martin2,3, Rafael Filippelli-Silva & Juliana Maria Ferraz Sallum1,4 Received: 8 June 2018 Accepted: 15 October 2018 Published: xx xx xxxx 2 , Mariana Vallim Salles 1 Among the Brazilian population, the frequency rates of inherited retinal dystrophies and their causative genes are underreported. To increase the knowledge about these dystrophies in our population, we retrospectively studied the medical records of 1,246 Brazilian patients with hereditary retinopathies during 20 years of specialized outpatient clinic care. Of these patients, 559 had undergone at least one genetic test. In this cohort, the most prevalent dystrophies were non-syndromic retinitis pigmentosa (35%), Stargardt disease (21%), Leber congenital amaurosis (9%), and syndromic inherited retinal dystrophies (12%). Most patients had never undergone genetic testing (55%), and among the individuals with molecular test results, 28.4% had negative or inconclusive results compared to 71.6% with a conclusive molecular diagnosis. ABCA4 was the most frequent disease-causing gene, accounting for 20% of the positive cases. Pathogenic variants also occurred frequently in the CEP290, USH2A, CRB1, RPGR, and CHM genes. The relative frequency rates of different inherited retinal dystrophies in Brazil are similar to those found globally. Although mutations in more than 250 genes lead to hereditary retinopathies, only 66 genes were responsible for 70% of the cases, which indicated that smaller and cheaper gene panels can be just as effective and provide more affordable solutions for implementation by the Brazilian public health system. It is estimated that 253 million people are visually impaired worldwide; the majority have moderate to severe visual impairment and 36 million are blind1. Among children under 15 years of age, approximately 14 million are blind globally2. In high- and middle-income countries, the most common causes of childhood blindness are cerebral visual impairment, optic nerve hypoplasia, and inherited retinal disorders3. Inherited retinal dystrophies (IRDs) constitute a group of diseases with vast clinical and genetic heterogeneity that affect about 1 in 2,000 to 3,000 individuals4. According to the Retinal Information Network5, more than 250 genes already have been implicated as causes of retinal diseases, many of which may cause more than one phenotype. The IRD features are related primarily to progressive retinal degeneration with significant decreases in or total loss of vision. The disease onset, progression, and severity vary and are difficult to predict. The modes of inheritance can range from autosomal dominant and recessive to X-linked6. The most common forms of IRDs are retinitis pigmentosa (RP), a rod-cone dystrophy that affects about 1 in ~4,000 individuals7 and can result from mutations in approximately 90 genes5, among them the ABCA4, BEST1, CERKL, CRB1, CRX, EYS, IFT140, MERTK, PDE6B, RHO, RP1, RP1L1, RP2, RPE65, RPGR, and USH2A genes; Stargardt disease (STGD), a type of macular dystrophy with a prevalence of 1 in 10,000 individuals8, that usually is caused by pathogenic variants in the ABCA49,10, ELOV411, or PROM112 genes; and Usher syndrome, the most frequent syndromic RP affecting 1 in 20,000 Caucasian individuals13, that has deafness as its main feature in association with visual impairment14,15 due to mutations in the ABHD12, ADGRV1, ARSG, CDH23, CEP250, CEP78, CIB2, CLRN1, DFNB31, HARS, MYO7A, PCDH15, USH1C, USH1G, and USH2A genes5. In Brazil, about 506,000 people are blind, of whom approximately 66,000 (13%) are children16. In 2012, the Brazilian Council of Ophthalmology estimated that about 50,000 people have RP17. In the Brazilian population, the frequency rate of IRDs and their causative genes are underreported. Our group published the only study that showed the relative frequency of retinopathies in southeastern Brazil18, with the results based only on the clinical diagnoses of 93 patients. The current study is the result of 20 years of care of patients with IRDs that describes the relative frequencies of different diseases, molecular diagnostic success rates, and disease-causing genes in the Brazilian population. 1 Department of Ophthalmology, Universidade Federal de São Paulo, São Paulo, Brazil. 2Department of Biophysics, Universidade Federal de São Paulo, São Paulo, Brazil. 3Institute of Genetic Medicine, Johns Hopkins Medicine, Baltimore, USA. 4Instituto de Genética Ocular, Sao Paulo, Brazil. Correspondence and requests for materials should be addressed to J.M.F.S. (email: ) SCIentIFIC RePorTS | (2018) 8:15939 | DOI:10.1038/s41598-018-34380-0 1 www.nature.com/scientificreports/ Figure 1. The distribution of patients according to their clinical diagnoses (n = 1,246). The syndromic IRD cases are grouped in the pie chart, and detailed in the stacked bar on the right. Arts syndrome, HallervordenSpatz disease, Jalili syndrome, Marshall syndrome, Microcephaly and chorioretinopathy and PHARC syndrome (Polyneuropathy, Hearing loss, Ataxia, Retinitis pigmentosa, and Cataract) are designated as “other syndromes”. Total Positive Results (%)* Molecular Test Total Patients aCGH 1 1 (100%) APEX 52 14 (26.9%) Exome 9 6 (66.7%) NGS panels 453 348 (76.8%) Sanger Sequencing 44 31 (70.5%) Table 1. Number of patients according to the sort of molecular test performed. The total number of patients that underwent molecular testing is 559, with positive results in 400. *Percentage based on the total number of patients who underwent molecular testing. aCGH: microarray comparative genomic hybridization; APEX: arrayed primer extension; NGS panels: next-generation sequencing gene panel. Results Clinical diagnosis. Over the previous 20 years, 1,246 patients with retinopathy who were members of 1,159 different families have been evaluated. Among the individuals, 906 were sporadic cases, 161 were related patients, and 179 had other affected relatives who were not included in this study. In addition, 122 (>10%) families had the feature of consanguinity. Most patients had non-syndromic RP (~35%), followed by patients with macular impairment caused by STGD (~21%) and patients with severe congenital and early-onset IRDs that represented approximately one-tenth of all cases (Leber congenital amaurosis [LCA], 9% and early-onset retinal dystrophy [EORD], ~2%) (Fig. 1). The syndromic forms of retinal dystrophies accounted for 12% of all patients in this study, wherein ciliopathies were more prominent, affecting 9.6% of the cases (Usher syndrome 6%, Bardet-Biedl syndrome 2.5%, Joubert syndrome 0.56%, Senior-Løken syndrome 0.32%, and Alström syndrome 0.24%) (Fig. 1). Among the metabolic disorders, neuronal ceroid lipofuscinosis was the most representative (0.72%). In this study, choroideremia was the only disease found among the chorioretinal (...truncated)