The cost of genetic diagnosis of suspected hereditary pediatric cataracts with whole-exome sequencing from a middle-income country perspective: a mixed costing analysis.

Up to 25% of pediatric cataract cases are inherited. There is sparse information in the literature regarding the cost of whole-exome sequencing (WES) for suspected hereditary pediatric cataracts. Molecular diagnosis of suspected hereditary pediatric cataracts is important for comprehensive genetic counseling. We performed a partial economic evaluation with a mixed costing analysis, using reimbursement data and microcosting approach with a bottom-up technique to estimate the cost of using WES for genetic diagnosis of suspected hereditary pediatric cataracts from the perspective of the Brazilian governmental health care system. One hundred and ten participants from twenty-nine families in Rio de Janeiro (RJ) were included. Costs of consumables, staff and equipment were calculated. Two scenarios were created: (1) The reference scenario included patients from RJ with suspected hereditary pediatric cataracts plus two family members. (2) The alternative scenario considered other genetic diseases, resulting in 5,280 exams per month. Sensitivity analysis was also performed. In the reference scenario, the total cost per exam was 700.09 United States dollars (USD), and in the alternative scenario, the total cost was 559.23 USD. The cost of WES alone was 527.85 USD in the reference scenario and 386.98 USD in the alternative scenario. Sensitivity analysis revealed that the largest costs were associated with consumables in both scenarios. Economic evaluations can help inform policy decisions, especially in middle-income countries such as Brazil.

Macular dystrophies associated with Stargardt-like phenotypes / Distrofias maculares associadas a fenótipos Stargardt-like

ABSTRACT Purpose: Stargardt-like phenotype has been described as associated with pathogenic variants besides the ABCA4 gene. This study aimed to describe four cases with retinal appearance of Stargardt disease phenotypes and unexpected molecular findings. Methods: This report reviewed medical records of four patients with macular dystrophy and clinical features of Stargardt disease. Ophthalmic examination, fundus imaging, and next-generation sequencing were performed to evaluate pathogenic variants related to the phenotypes. Results: Patients presented macular atrophy and pigmentary changes suggesting Stargardt disease. The phenotypes of the two patients were associated with autosomal dominant inheritance pattern genes (RIMS1 and CRX) and in the other two patients were associated with recessive dominant inheritance pattern genes (CRB1 and RDH12) with variants predicted to be pathogenic. Conclusion: Macular dystrophies may have phenotypic similarities to Stargardt-like phenotype associated with other genes besides the classic ones.

RESUMO Objetivo: Fenótipos Stargardt-like já foram asso-ciados a variantes patogênicas no gene ABCA4. O propósito desse estudo é descrever quatro pacientes com achados retinianos semelhantes a doença de Stargardt com resultados moleculares diferentes do esperado. Métodos: Esse relato fez a revisão de prontuários médicos de quatro pacientes com distrofia macular e achados clínicos sugestivos de doença de Stargardt. Foram realizados avaliação oftalmológica, exames de imagens e testes usando next generation sequencing para avaliar variantes patogênicas associadas aos fenótipos dos pacientes. Resultados: Os pacientes apresentavam atrofia macular e alterações pigmentares sugerindo achados clínicos de doença de Stargardt. Dois pacientes foram associados a genes com herança autossômica dominante (RIMS1 e CRX) e dois pacientes foram associados a genes com herança autossômica recessiva (CRB1 e RDH12) com variantes preditoras de serem patogênicas. Conclusão: Distrofias maculares podem ter similaridades fenotípicas com fenótipo de Stargardt-like associados a outros genes além dos classicamente já descritos.

Genotypic-Phenotypic Correlations of Hereditary Hyperferritinemia-Cataract Syndrome: Case Series of Three Brazilian Families.

Hereditary hyperferritinemia-cataract syndrome (HHCS) is a rare, frequently misdiagnosed, autosomal dominant disease caused by mutations in the FTL gene. It causes bilateral pediatric cataract and hyperferritinemia without iron overload. The objective of this case series, describing three Brazilian families, is to increase awareness of HHCS, as well as to discuss possible phenotypic interactions with concurrent mutations in HFE, the gene associated with autosomal recessive inheritance hereditary hemochromatosis. Whole-exome sequencing was performed in eight individuals with HHCS from three different families, as well as one unaffected member from each family for trio analysis-a total of eleven individuals. Ophthalmological and clinical genetic evaluations were conducted. The likely pathogenic variant c.-157G>A in FTL was found in all affected individuals. They presented slowly progressing bilateral cataract symptoms before the age of 14, with a phenotype of varied bilateral diffuse opacities. Hyperferritinemia was present in all affected members, varying from 971 ng/mL to 4899 ng/mL. There were two affected individuals with one concurrent pathogenic variant in HFE (c.187C>G, p.H63D), who were also the ones with the highest values of serum ferritin in our cohort. Few publications describe individuals with pathogenic mutations in both FTL and HFE genes, and further studies are needed to assess possible phenotypic interactions causing higher values of hyperferritinemia.

Molecular and Clinical Characterization of CNGA3 and CNGB3 Genes in Brazilian Patients Affected with Achromatopsia.

Achromatopsia (ACHM) is a congenital cone photoreceptor disorder characterized by reduced visual acuity, nystagmus, photophobia, and very poor or absent color vision. Pathogenic variants in six genes encoding proteins composing the cone phototransduction cascade (CNGA3, CNGB3, PDE6C, PDE6H, GNAT2) and of the unfolded protein response (ATF6) have been related to ACHM cases, while CNGA3 and CNGB3 alone are responsible for most cases. Herein, we provide a clinical and molecular overview of 42 Brazilian patients from 38 families affected with ACHM related to biallelic pathogenic variants in the CNGA3 and CNGB3 genes. Patients' genotype and phenotype were retrospectively evaluated. The majority of CNGA3 variants were missense, and the most prevalent CNGB3 variant was c.1148delC (p.Thr383Ilefs*13), resulting in a frameshift and premature stop codon, which is compatible with previous publications in the literature. A novel variant c.1893T>A (p.Tyr631*) in the CNGB3 gene is reported for the first time in this study. A great variability in morphologic findings was observed in our patients, although no consistent correlation with age and disease stage in OCT foveal morphology was found. The better understanding of the genetic variants landscape in the Brazilian population will help in the diagnosis of this disease.

Macular dystrophies associated with Stargardt-like phenotypes.

PURPOSE: Stargardt-like phenotype has been described as associated with pathogenic variants besides the ABCA4 gene. This study aimed to describe four cases with retinal appearance of Stargardt disease phenotypes and unexpected molecular findings. METHODS: This report reviewed medical records of four patients with macular dystrophy and clinical features of Stargardt disease. Ophthalmic examination, fundus imaging, and next-generation sequencing were performed to evaluate pathogenic variants related to the phenotypes. RESULTS: Patients presented macular atrophy and pigmentary changes suggesting Stargardt disease. The phenotypes of the two patients were associated with autosomal dominant inheritance pattern genes (RIMS1 and CRX) and in the other two patients were associated with recessive dominant inheritance pattern genes (CRB1 and RDH12) with variants predicted to be pathogenic. CONCLUSION: Macular dystrophies may have phenotypic similarities to Stargardt-like phenotype associated with other genes besides the classic ones.

Investigation of the photocatalytic and optical properties of the SrMoO4/g-C3N4 heterostructure obtained via sonochemical synthesis with temperature control.

In this work, nanomaterials of the SrMoO4/g-C3N4 heterostructure were synthesized in a single step by the sonochemical method with controlled temperatures. Structural and morphological investigations indicate the formation of heterojunctions, revealing the presence of g-C3N4 (CN) in the heterostructures and an interface region between the phases. Optical analyzes show broadening of the wavelength absorption range and a decrease in the photoluminescence (PL) intensity of the heterojunctions compared to the CN emission spectrum, proving a decrease in the recombination of the photogenerated charges. The results of the photocatalytic tests indicate that the insertion of CN promoted photocatalytic degradation of the Methylene Blue (MB), Rhodamine B (RhB) and Crystal Violet (CV) organic contaminants, up to 99.58%, 100% and 98.65%, respectively. The mixture of dyes used and reuse cycles was performed to analyze the applicability of the compounds in a real situation.

Multidisciplinary team directed analysis of whole genome sequencing reveals pathogenic non-coding variants in molecularly undiagnosed inherited retinal dystrophies.

The purpose of this paper is to identify likely pathogenic non-coding variants in inherited retinal dystrophy (IRD) genes, using genome sequencing (GS). Patients with IRD were recruited to the study and underwent comprehensive ophthalmological evaluation and GS. The results of GS were investigated through virtual gene panel analysis, and plausible pathogenic variants and clinical phenotype evaluated by the multidisciplinary team (MDT) discussion. For unsolved patients in whom a specific gene was suspected to harbor a missed pathogenic variant, targeted re-analysis of non-coding regions was performed on GS data. Candidate variants were functionally tested by messenger RNA analysis, minigene or luciferase reporter assays. Previously unreported, likely pathogenic, non-coding variants in 7 genes (PRPF31, NDP, IFT140, CRB1, USH2A, BBS10 and GUCY2D), were identified in 11 patients. These were shown to lead to mis-splicing (PRPF31, IFT140, CRB1 and USH2A) or altered transcription levels (BBS10 and GUCY2D). MDT-led, phenotype-driven, non-coding variant re-analysis of GS is effective in identifying the missing causative alleles.

A rare canonical splice-site variant in VPS13B causes attenuated Cohen syndrome.

BACKGROUND: To describe a patient with a history of obesity, retinal dystrophy, type II diabetes, and mild cognitive impairment; found to harbour biallelic splice-site variants in VPS13B. MATERIALS & METHODS: A complete ophthalmic evaluation was performed at Moorfields Eye Hospital (London, United Kingdom), consisting of measurement of best-corrected visual acuity (BCVA), slit lamp and dilated fundus evaluation, colour, autofluorescence and near-infrared retinal imaging, spectral domain-optical coherence tomography, and electroretinogram (ERG). Whole-genome sequencing was performed as part of the UK's 100,000 Genomes Project. RESULTS: A 26-year-old Pakistani man with normal appearance, stature, and head size presented with decreased BCVA and severely constricted visual fields to our Ophthalmic Genetics clinic. He had a history of obesity, type II diabetes, and mild cognitive impairment. His evaluation showed retina-wide, severe photoreceptor dysfunction in both eyes, with undetectable scotopic and photopic ERG waveforms. Genomic analysis identified a homozygous rare splice donor variant in the VPS13B gene (c.5024+2T>C) that was demonstrated to lead to skipping of the in-frame exon 31 (p.Gln1607_Ser1675delinsHis). CONCLUSIONS: Exon 31 skipping in VPS13B may lead to a hypomorphic change, with partial gene function and an incomplete, mild Cohen syndrome-like phenotype.

Novel Mutation in CRYBB3 Causing Pediatric Cataract and Microphthalmia.

Up to 25% of pediatric cataract cases are inherited, with half of the known mutant genes belonging to the crystallin family. Within these, crystallin beta B3 (CRYBB3) has the smallest number of reported variants. Clinical ophthalmological and genetic-dysmorphological evaluation were performed in three autosomal dominant family members with pediatric cataract and microphthalmia, as well as one unaffected family member. Peripheral blood was collected from all participating family members and next-generation sequencing was performed. Bioinformatics analysis revealed a novel missense variant c.467G>A/p.Gly156Glu in CRYBB3 in all family members with childhood cataract. This variant is classified as likely pathogenic by ACMG, and no previous descriptions of it were found in ClinVar, HGMD or Cat-Map. The only other mutation previously described in the fifth exon of CRYBB3 is a missense variant that causes a change in amino acid from the same 156th amino acid to arginine and has been associated with pediatric cataract and microphthalmia. To the best of our knowledge, this is the first time the c.467G>A/p.Gly156Glu variant is reported and the second time a mutation in CRYBB3 has been associated with microphthalmia.

Expanding the Phenotypic and Genotypic Spectrum of Bietti Crystalline Dystrophy.

The rare form of retinal dystrophy, Bietti crystalline dystrophy, is associated with variations in CYP4V2, a member of the cytochrome P450 family. This study reports patients affected by typical and atypical Bietti crystalline dystrophy, expanding the spectrum of this disease. This is an observational case series of patients with a clinical and molecular diagnosis of Bietti crystalline dystrophy that underwent multimodal imaging. Four unrelated patients are described with two known variants, c.802-8_810del17insGC and c.518T > G (p.Leu173Trp), and one novel missense variant, c.1169G > T (p.Arg390Leu). The patient with the novel homozygous variant had the most severe phenotype resulting in macular hole formation and retinal detachment in both eyes. To the best of our knowledge, there is no association of these features with Bietti crystalline dystrophy. Patient 1 was the youngest patient and had the mildest phenotype with crystals in the retina without chorioretinal atrophy and visual complaints. Patients 2 and 3 presented with fewer crystals and chorioretinal atrophy. These three patients presented a classic phenotype. The fourth patient presented with an atypical and severe phenotype. This study reveals a new genotype and new phenotype associated with this disorder.

Analysis of an NGS retinopathy panel detects chromosome 1 uniparental isodisomy in a patient with RPE65-related leber congenital amaurosis.

Purpose: This study aims to demonstrate the possibility of detecting segmental uniparental isodisomy (iUPD) using a next-generation sequencing gene panel by reporting a Leber congenital amaurosis (LCA) case caused by a homozygous pathogenic variant in RPE65 (c.1022 T > C:p.Leu341Ser) inherited exclusively from the proband's mother.Methods: Samples from the trio (proband, mother, and father) were sequenced with a next-generation sequencing (NGS) retinopathy gene panel (224 genes) and the VCF file containing all variants was used in order to determine single nucleotide variant (SNV) counts from each sample across all chromosomes.Results: Trio analysis showed that of 81 Chr1 inherited variants 41 were exclusively maternal, including 21 homozygous. The other 40 variants were common to both parents. On remaining autosomal chromosomes (Chr2-22) 645 inherited variants were found, 147 of them were exclusively maternal and 132 exclusively paternal. Based on these NGS data, it was possible to note that the proband's chromosomes 1 are more similar to his mother's chromosome 1 than his father's, suggesting the pathogenic homozygous variant found in this patient was inherited exclusively from the mother due to uniparental maternal isodisomy.Conclusions: This study presents a secondary analysis pipeline to identify responsible variants for a phenotype and the correct inheritance pattern, which is a critical step to the proper and accurate genetic counseling of all family members. In addition, this approach could be used to determine iUPD in different Mendelian disorders if the sequencing panel identifies variants spread throughout the genome.

Clinical and molecular findings in a cohort of 152 Brazilian severe early onset inherited retinal dystrophy patients.

Leber congenital amaurosis (LCA) and early-onset retinal dystrophy (EORD) are severe inherited retinal dystrophy that can cause deep blindness childhood. They represent 5% of all retinal dystrophies in the world population and about 10% in Brazil. Clinical findings and molecular basis of syndromic and nonsyndromic LCA/EORD in a Brazilian sample (152 patients/137 families) were studied. In this population, 15 genes were found to be related to the phenotype, 38 new variants were detected and four new complex alleles were discovered. Among 123 variants found, the most common were CEP290: c.2991+1655A>G, CRB1: p.Cys948Tyr, and RPGRIP1: exon10-18 deletion.

Zirconia/hydroxyapatite (80/20) scaffold repair in critical size calvarial defect increased FGF-2, osteocalcin and OPG immunostaining and IL-10 levels.

The aim of this study was to characterize and evaluate zirconia/hydroxyapatite in a critical size calvarial defect model in rats. Zirconia/hydroxyapatite (80/20) scaffold was characterized by X-ray diffraction (XRD) and Scanning Electron Microscopy (SEM). Critical size (8 mm) calvarial defects were created in wistar rats (n=48) and divided into four groups (90 days): G0 Group: positive control; G1 Group: hydroxyapatite; G2 Group: Zirconia; G3 Group: Zirconia/hydroxyapatite (80/20). Calvaria were subjected to Micro CT, histological and immunohistochemical analyses (RANK, RANKL, OPG, osteocalcin and FGF-2). IL-1 beta, IL-10 and TNF-alpha levels were analyzed by Elisa Immunoassay. The XRD analysis confirmed the formation of a crystalline structure and SEM showed the presence of regions corresponding to Zirconia and Hydroxyapatite. The Micro CT showed increased bone volume (BV/TV) and bone mineral density (BMD) in the G3 group (P<0.05). In addition, discrete periosteal bone formation was found at the interface of the defect edge and the external surface of the scaffold in the G3 group, showing osteocytes inside and osteoblasts (P<0.05) with scarce mononuclear inflammatory cells (P<0.01) in the central region of the defect. The immunostaining was moderate for RANKL, Osteocalcin and FGF-2 in the G3 group (P<0.5), while it was intense for OPG (P<0.001). IL-1 beta levels were decreased and IL-10 levels increased (P<0.05). Zirconia/hydroxyapatite (80/20) scaffold repair in critical size calvarial defects increased bone density, osteoblast and osteoclast cell numbers, FGF-2, osteocalcin and OPG immunostaining and IL-10 levels.

TUBGCP4 - associated microcephaly and chorioretinopathy.

Background Microcephaly and chorioretinopathy (MCCRP) is a rare neuro-ophthalmologic disorder that causes microcephaly and chorioretinopathy. In a recessive inheritance pattern, there are three types: MCCRP1; MCCRP2 and MCCRP3. MCCRP3 results from pathogenic variants in the tubulin-gamma complex-associated protein 4 (TUBGCP4) gene.Materials and Methods This is a case report of a patient with a molecular diagnosis defined by mutations in the TUBGCP4 gene. Segregation analyses were carried out.Results The molecular investigation found two heterozygous variants c.1380 G > A (p.Trp460*) a novel nonsense variant, and c.1746 G > T (p Leu582=) a synonymous variant in TUBGCP4. The clinical phenotype was characterized by microcephaly, microphthalmia, chorioretinopathy, a punched-out retinal appearance, dysmorphic facial features, decreased visual acuity, and learning difficulties. The clinical features were similar to those described previously in children with MCCRP3. The proband also had additional features including centripetal obesity, stretch marks, acanthosis nigricans, scoliosis, and hypercholesterolemia. These other features could be part of a ciliopathy syndrome.Conclusions MCCRP2 caused by pathogenic variants in PLK4 is well established as a ciliopathy disease. The role of TUBGCP4 is not well established in the cilium physiology. MCCRP3 may be part of the ciliopathy spectrum.

Synonymous Variant in the CHM Gene Causes Aberrant Splicing in Choroideremia.

Purpose: Choroideremia is an inherited retinal degeneration caused by 280 different pathogenic variants in the CHM gene. Only one silent/synonymous variant (c.1359C>T; p.(Ser453=)) has been reported and was classified as inconclusive based on in silico analysis. This study elucidates the pathogenicity of this variant also found in a Brazilian patient. Methods: Ophthalmological examinations such as color fundus photography, spectral-domain optical coherence tomography, fundus autofluorescence, and macular integrity assessment microperimetry were performed. The subjects' total RNA was extracted from peripheral blood cells. cDNA was synthesized and the amplification between exon 10 and 14 of the CHM mRNA was performed. The amplification products were sequenced by Sanger sequencing and the results were aligned to the reference sequence. Results: The synonymous variant c.1359C>T p.(Ser453=) in the CHM gene is associated with an error in mRNA processing, leading preferentially to production of an aberrant transcript without exon 11 (p.(Gln451Phefs*3)). This anomalous mRNA production is related to typical choroideremia phenotype. Conclusions: These molecular findings reinforce the need for more detailed investigation of silent variants in patients with well-defined phenotype of retinal dystrophies. Molecular and clinical findings provided evidence that c.1359C>T (p.(Gln451Phefs*3)) in CHM should be considered a disease-causing variant.

Retinitis Pigmentosa Due to Rp1 Biallelic Variants.

In the present study, we screened 529 Brazilian individuals affected by inherited retinal disorders. A total of seven unrelated and nonsyndromic patients with RP1 biallelic variants (OMIM # 180100) were diagnosed in our centre and included in the study. They had classic retinitis pigmentosa with diagnosis at the first decade of life. The visual acuities were severely affected at a young age. The fundus aspects were similar among all patients. An atrophic ring was present around the fovea in several cases. All patients had molecular diagnosis, with six different RP1 variants. This study reports two new pathogenic variants - two frameshift duplications (c.1234dupA p.Met412Asnfs*7 and c.1265dupC p.Ala423Cysfs*2) and reinforces other four known pathogenic variants - two frameshift deletions (c.469delG p.Val157Trpfs*16 and c.3843delT p.Pro1282Leufs*12) and two stop gain mutations (c.1186 C > T p.Arg396* and c.1625C > G p.Ser542*). These findings broaden the spectrum of RP1 variants. This study also reviewed the fundus characteristics that clinically could raise the hypothesis of a retinitis pigmentosa due to RP1 gene. It is worthwhile to try to identify the disease-causing variants in each patient since it can provide prognostic information and be useful in genetic consultation and diagnosis in the future.

Correlation between GLA variants and alpha-Galactosidase A profile in dried blood spot: an observational study in Brazilian patients.

BACKGROUND: Fabry disease is a rare X-linked inherited disorder caused by deficiency of α-Galactosidase A. Hundreds of mutations and non-coding haplotypes in the GLA gene have been described; however, many are variants of unknown significance, prompting doubts about the diagnosis and treatment. The α-Galactosidase A enzymatic activity in dried blood spot (DBS) samples are widely used for screening purposes; however, even when values below the normal are found, new tests are required to confirm the diagnosis. Here we describe an analysis of GLA variants and their correlation with DBS α-Galactosidase A enzymatic activity in a large Brazilian population with Fabry disease symptoms. RESULTS: We analyzed GLA variants by DNA sequencing of 803 male patients with suspected Fabry disease or belonging to high-risk populations; in 179 individuals, 58 different exonic variants were detected. From these, 50 are variants described as pathogenic and eight described as variants of unknown significance. The other individuals presented complex non-coding haplotypes or had no variants. Interestingly, the enzymatic activity in DBS was different among pathogenic variants and the other genotypes, including variants of unknown significance; the first presented mean of 12% of residual activity, while the others presented levels above 70% of the activity found in healthy controls. CONCLUSION: The activity of α-Galactosidase A in DBS was markedly reduced in males with known pathogenic variants when compared with subjects presenting variants of unknown significance, non-coding haplotypes, or without variants, indicating a possible non-pathogenic potential of these latter genotypes. These findings bring a better understanding about the biochemical results of α-Galactosidase A in DBS samples, as well as the possible non-pathogenic potential of non-coding haplotypes and variants of unknown significance in GLA gene. These results certainly will help clinicians to decide about the treatment of patients carrying variants in the gene causing this rare but life-threatening disease.

Integration of experiment and computational modeling on the Tb doping process in CaMoO4 obtained by USP method: An efficient way to obtain photoluminescent materials.

In this paper, we present a combined experimental and theoretical study to disclose, the structure, electronic and optical properties of CaMoO 4 :xTb 3+ ( x = 1%, 2%, and 4%) microspheres. The microspheres were prepared by ultrasonic spray pyrolysis method and characterized by experimental and theoretical techniques. Theoretical calculations and XRD patterns indicate that these crystals have a scheelite-type tetragonal structure. The morphology of the CaMoO 4 :xTb 3+ ( x = 1%, 2% and 4% mol) samples were investigated from the FEG-SEM results and the formation of microspheres with a spherical shape were observed. The optical properties were investigated by UV-Vis and PL spectroscopy, as well as the chromaticity coordinates of these compounds. This also allowed us to understand the charge transfer process that happens in the singlet state and the excited states, generating the photoluminescence emissions of the Tb doping process in CaMoO 4 microspheres.

Pathogenicity Reclasssification of RPE65 Missense Variants Related to Leber Congenital Amaurosis and Early-Onset Retinal Dystrophy.

A challenge in molecular diagnosis and genetic counseling is the interpretation of variants of uncertain significance. Proper pathogenicity classification of new variants is important for the conclusion of molecular diagnosis and the medical management of patient treatments. The purpose of this study was to reclassify two RPE65 missense variants, c.247T>C (p.Phe83Leu) and c.560G>A (p.Gly187Glu), found in Brazilian families. To achieve this aim, we reviewed the sequencing data of a 224-gene retinopathy panel from 556 patients (513 families) with inherited retinal dystrophies. Five patients with p.Phe83Leu and seven with p.Gly187Glu were selected and their families investigated. To comprehend the pathogenicity of these variants, we evaluated them based on the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) classification guidelines. Initially, these RPE65 variants met only three pathogenic criteria: (i) absence or low frequency in the population, (ii) several missense pathogenic RPE65 variants, and (iii) 15 out of 16 lines of computational evidence supporting them as damaging, which together allowed the variants to be classified as uncertain significance. Two other pieces of evidence were accepted after further analysis of these Brazilian families: (i) p.Phe83Leu and p.Gly187Glu segregate with childhood retinal dystrophy within families, and (ii) their prevalence in Leber congenital amaurosis (LCA)/early-onset retinal dystrophy (EORD) patients can be considered higher than in other inherited retinal dystrophy patients. Therefore, these variants can now be classified as likely pathogenic according to ACMG/AMP classification guidelines.

Retinal dystrophies and variants in PRPH2 / Distrofias retinianas e variantes em PRPH2

ABSTRACT - This report presents three patients diagnosed with macular dystrophies with variants in PRPH2. Peripherin-2, the protein of this gene, is important in the morphogenesis and stabilization of the photoreceptor outer segment. Peripherin-2 deficiencies cause cellular apoptosis. Moreover, pathogenic variants in PRPH2 are associated with various diseases, such as pattern, butterfly-shaped pattern, central areolar, adult-onset vitelliform macular, and cone-rod dystrophies as well as retinitis pigmentosa, retinitis punctata albescens, Leber congenital amaurosis, fundus flavimaculatus, and Stargardt disease.

RESUMO - Este relato apresenta três pacientes com diagnóstico de distrofias maculares com mutações no PRPH2. Periferina 2, a proteína deste gene, é importante na morfogênese e estabilização do segmento externo dos fotorreceptores. Deficiências de periferina 2 causam apoptose celular. Além disso, variantes patogênicas no PRPH2 estão relacionadas a diferentes doenças, como distrofia padrão, distrofia padrão em asa de borboleta, distrofia central areolar, distrofia viteliforme do adulto, retinose pigmentar, distrofia de cones e bastonetes, retinite punctata albscens, amaurose congênita de Leber, fundus flavimaculatus e doença de Stargardt.