Research

19 pages, 2986 KiB

Open AccessArticle

Occult Macular Dysfunction Syndrome: Identification of Multiple Pathologies in a Clinical Spectrum of Macular Dysfunction with Normal Fundus in East Asian Patients: EAOMD Report No. 5

by Yu Fujinami-Yokokawa, Lizhu Yang, Kwangsic Joo, Kazushige Tsunoda, Xiao Liu, Mineo Kondo, Seong Joon Ahn, Hui Li, Kyu Hyung Park, Hisateru Tachimori, Hiroaki Miyata, Se Joon Woo, Ruifang Sui and Kaoru Fujinami

Genes 2023, 14(10), 1869; https://doi.org/10.3390/genes14101869 - 26 Sep 2023

Cited by 1 | Viewed by 1030

Abstract

Occult macular dystrophy (OMD) is the most prevalent form of macular dystrophy in East Asia. Beyond RP1L1, causative genes and mechanisms remain largely uncharacterised. This study aimed to delineate the clinical and genetic characteristics of OMD syndrome (OMDS). Patients clinically diagnosed with [...] Read more.

Occult macular dystrophy (OMD) is the most prevalent form of macular dystrophy in East Asia. Beyond RP1L1, causative genes and mechanisms remain largely uncharacterised. This study aimed to delineate the clinical and genetic characteristics of OMD syndrome (OMDS). Patients clinically diagnosed with OMDS in Japan, South Korea, and China were enrolled. The inclusion criteria were as follows: (1) macular dysfunction and (2) normal fundus appearance. Comprehensive clinical evaluation and genetic assessment were performed to identify the disease-causing variants. Clinical parameters were compared among the genotype groups. Seventy-two patients with OMDS from fifty families were included. The causative genes were RP1L1 in forty-seven patients from thirty families (30/50, 60.0%), CRX in two patients from one family (1/50, 2.0%), GUCY2D in two patients from two families (2/50, 4.0%), and no genes were identified in twenty-one patients from seventeen families (17/50, 34.0%). Different severities were observed in terms of disease onset and the prognosis of visual acuity reduction. This multicentre large cohort study furthers our understanding of the phenotypic and genotypic spectra of patients with macular dystrophy and normal fundus. Evidently, OMDS encompasses multiple Mendelian retinal disorders, each representing unique pathologies that dictate their respective severity and prognostic patterns. Full article

(This article belongs to the Special Issue Study of Inherited Retinal Diseases)

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19 pages, 6013 KiB

Open AccessArticle

XLRS Rat with Rs1^-/Y Exon-1-Del Shows Failure of Early Postnatal Outer Retina Development

by Eun-Ah Ye, Yong Zeng, Serafina Thomas, Ning Sun, Zeljka Smit-McBride and Paul A. Sieving

Genes 2022, 13(11), 1995; https://doi.org/10.3390/genes13111995 - 31 Oct 2022

Cited by 1 | Viewed by 1671

Abstract

We generated a Long Evans transgenic rat with targeted deletion of the whole Rs1 exon-1 and evaluated the pathological retinal phenotype of this Rs1^-/Y rat model of X-linked retinoschisis (XLRS). The Rs1^−/Y rat exhibited very early onset and rapidly progressive photoreceptor [...] Read more.

We generated a Long Evans transgenic rat with targeted deletion of the whole Rs1 exon-1 and evaluated the pathological retinal phenotype of this Rs1^-/Y rat model of X-linked retinoschisis (XLRS). The Rs1^−/Y rat exhibited very early onset and rapidly progressive photoreceptor degeneration. The outer limiting membrane (OLM) was disrupted and discontinuous by post-natal day (P15) and allowed photoreceptor nuclei to dislocate from the outer nuclear layers (ONL) into the sub-retinal side of the OLM. Dark-adapted electroretinogram (ERG) a-wave and b-wave amplitudes were considerably reduced to only 20–25% of WT by P17. Microglia and Müller glial showed cell marker activation by P7. Intravitreal application of AAV8-RS1 at P5–6 induced RS1 expression by P15 and rescued the inner nuclear layer (INL) and outer plexiform layer (OPL) cavity formation otherwise present at P15, and the outer-retinal structure was less disrupted. This Rs1^−/Y exon-1-del rat model displays substantially faster rod cell loss compared to the exon-1-del Rs1-KO mouse. Most unexpected was the rapid appearance of schisis cavities between P7 and P15, and then cavities rapidly disappeared by P21/P30. The rat model provides clues on the molecular and cellular mechanisms underlying XLRS pathology in this model and points to a substantial and early changes to normal retinal development. Full article

(This article belongs to the Special Issue Study of Inherited Retinal Diseases)

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15 pages, 5281 KiB

Open AccessArticle

A Novel Hypothesis on Choroideremia-Manifesting Female Carriers: Could CHM In-Frame Variants Exert a Dominant Negative Effect? A Case Report

by Niccolò Di Giosaffatte, Michele Valiante, Stefano Tricarico, Giulia Parise, Anna Maria De Negri, Guido Ricciotti, Lara Florean, Alessandro Paiardini, Irene Bottillo and Paola Grammatico

Genes 2022, 13(7), 1268; https://doi.org/10.3390/genes13071268 - 17 Jul 2022

Cited by 4 | Viewed by 1695

Abstract

Choroideremia is an X-linked recessive condition presenting in males, with progressive degeneration of retinal and choroidal tissues leading to progressive visual loss. Its pathological mechanism is due to alterations in the CHM gene that encodes for REP1, a protein required for prenylation of [...] Read more.

Choroideremia is an X-linked recessive condition presenting in males, with progressive degeneration of retinal and choroidal tissues leading to progressive visual loss. Its pathological mechanism is due to alterations in the CHM gene that encodes for REP1, a protein required for prenylation of Rab by the Rab geranylgeranyl transferase (RGGT). Even though female carriers are predicted to be not affected by the disease, a wide phenotypic spectrum ranging from mild to severe cases has been reported in women. The reason why Choroideremia manifests in female carriers remains elusive. While X chromosome inactivation (XCI) skewing has been proposed as a leading putative mechanism, emerging evidence has shown that CHM could variably escape from XCI. We described a family with an initial clinical suspicion of Retinitis Pigmentosa in which a novel CHM pathogenic splicing variant was found by exome sequencing. The variant, initially found in the 63-year-old female presenting with impaired visual acuity and severe retinal degeneration, segregated in the 31-year-old daughter and the 37-year-old son, both presenting with fundus anomalies. mRNA studies revealed a shorter in-frame CHM isoform lacking exon 10. Molecular modeling of the ternary REP1/Rab/RGGT protein complex predicted significant impairing of REP1/Rab binding without alteration of REP1/RGGT interaction. We suggest that, in our female cases, the biallelic expression of CHM may have led to the production of both the mutant and wild type REP1. The mutant isoform, sequestrating RGGT, could reduce its available amount for Rab prenylation, thus exerting a dominant-negative effect. If confirmed with further studies and in large cohorts of female carriers, the here proposed molecular mechanism could help to explain the complexity of manifestation of Choroideremia in females. Full article

(This article belongs to the Special Issue Study of Inherited Retinal Diseases)

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10 pages, 1212 KiB

Open AccessArticle

Clinical Features and Genetic Findings of Autosomal Recessive Bestrophinopathy

by Hae Rang Kim, Jinu Han, Yong Joon Kim, Hyun Goo Kang, Suk Ho Byeon, Sung Soo Kim and Christopher Seungkyu Lee

Genes 2022, 13(7), 1197; https://doi.org/10.3390/genes13071197 - 04 Jul 2022

Cited by 2 | Viewed by 1715

Abstract

Autosomal recessive bestrophinopathy (ARB) is a rare subtype of bestrophinopathy caused by biallelic mutations of the BEST1 gene. ARB is characterized by multifocal subretinal deposits accompanied by macular edema or subretinal fluid, hyperopia, co-existing narrow angle, and a marked decrease in electrooculogram. However, [...] Read more.

Autosomal recessive bestrophinopathy (ARB) is a rare subtype of bestrophinopathy caused by biallelic mutations of the BEST1 gene. ARB is characterized by multifocal subretinal deposits accompanied by macular edema or subretinal fluid, hyperopia, co-existing narrow angle, and a marked decrease in electrooculogram. However, little is known about the genetic variants and specific clinical features of ARB. This is an observational case series of patients with a clinical and genetic diagnosis of ARB who underwent multimodal imaging. We describe ten patients from nine unrelated families with six known variants and three novel missense variants: c.236C→T, p.(Ser79Phe); C.452C→T, p.(Leu151Pro); and c.650C→T, p.(Trp217Met). The most common variant was c.584C→T, p.(Ala195Val), observed in six patients, without correlation to the severity of the phenotype. All patients manifested bilateral multifocal subretinal deposits and subretinal fluid throughout the follow-up period, while intraretinal fluid was found in approximately half of the eyes. The extent or chronicity of the fluid collection did not correlate with visual acuity. Angle-closure glaucoma was present in five eyes. Three patients had a genetically confirmed family history of ARB, and one patient had a clinically suspected family history. This study reveals novel mutations in the BEST1 gene and adds to the spectrum of clinical presentations of ARB. Full article

(This article belongs to the Special Issue Study of Inherited Retinal Diseases)

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18 pages, 1066 KiB

Open AccessArticle

A Survey of Multigenic Protein-Altering Variant Frequency in Familial Exudative Vitreo-Retinopathy (FEVR) Patients by Targeted Sequencing of Seven FEVR-Linked Genes

by Amanda Petrelli Cicerone, Wendy Dailey, Michael Sun, Andrew Santos, Daeun Jeong, Lance Jones, Konstaninos Koustas, Mary Drekh, Keaton Schmitz, Naomi Haque, Jennifer A. Felisky, Alvaro E. Guzman, Kendra Mellert, Michael T. Trese, Antonio Capone, Kimberly A. Drenser and Kenneth P. Mitton

Genes 2022, 13(3), 495; https://doi.org/10.3390/genes13030495 - 11 Mar 2022

Cited by 7 | Viewed by 15858

Abstract

While Inherited Retinal Diseases (IRDs) are typically considered rare diseases, Familial Exudative Vitreo-Retinopathy (FEVR) and Norrie Disease (ND) are more rare than retinitis pigmentosa. We wanted to determine if multigenic protein-altering variants are common in FEVR subjects within a set of FEVR-related genes. [...] Read more.

While Inherited Retinal Diseases (IRDs) are typically considered rare diseases, Familial Exudative Vitreo-Retinopathy (FEVR) and Norrie Disease (ND) are more rare than retinitis pigmentosa. We wanted to determine if multigenic protein-altering variants are common in FEVR subjects within a set of FEVR-related genes. The potential occurrence of protein-altering variants in two different genes has been documented in a very small percentage of patients, but potential multigenic contributions to FEVR remain unclear. Genes involved in these orphan pediatric retinal diseases are not universally included in available IRD targeted-sequencing panels, and cost is also a factor limiting multigenic-sequence-based testing for these rare conditions. To provide an accurate solution at lower cost, we developed a targeted-sequencing protocol that includes seven genes involved in Familial Exudative Vitreo-Retinopathy (FEVR) and Norrie disease. Seventy-six DNA samples from persons refered to clinic with possible FEVR and some close relatives were sequenced using a novel Oakland-ERI orphan pediatric retinal disease panel (version 2) providing 900 times average read coverage. The seven genes involved in FEVR/ND were: NDP (ChrX), CTNNB1 (Chr3); TSPAN12 (Chr7); KIF11 (Chr10), FZD4 (Chr11), LRP5 (Chr11), ZNF408 (Chr11). A total of 33 variants were found that alter protein sequence, with the following relative distribution: LRP5 13/33 (40%), FZD4 9/33 (27%), ZNF408 6/33 (18%), (KIF11 3/33 (9%), NDP 1/33 (3%), CTNNB1 1/33 (3%). Most protein-altering variants, 85%, were found in three genes: FZD4, LRP5, and ZNF408. Four previously known pathogenic variants were detected in five families and two unrelated individuals. Two novel, likely pathogenic variants were detected in one family (FZD4: Cys450ter), and a likely pathogenic frame shift termination variant was detected in one unrelated individual (LRP5: Ala919CysfsTer67). The average number of genes with protein-altering variants was greater in subjects with confirmed FEVR (1.46, n = 30) compared to subjects confirmed unaffected by FEVR (0.95, n = 20), (p = 0.009). Thirty-four percent of persons sequenced had digenic and trigenic protein-altering variants within this set of FEVR genes, which was much greater than expected in the general population (3.6%), as derived from GnomAD data. While the potential contributions to FEVR are not known for most of the variants in a multigenic context, the high multigenic frequency suggests that potential multigenic contributions to FEVR severity warrant future investigation. The targeted-sequencing format developed will support such exploration by reducing the testing cost to $250 (US) for seven genes and facilitating greater access to genetic testing for families with this very rare inherited retinal disease. Full article

(This article belongs to the Special Issue Study of Inherited Retinal Diseases)

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14 pages, 2277 KiB

Open AccessArticle

Maternal Uniparental Isodisomy of Chromosome 4 and 8 in Patients with Retinal Dystrophy: SRD5A3-Congenital Disorders of Glycosylation and RP1-Related Retinitis Pigmentosa

by Nobutaka Tachibana, Katsuhiro Hosono, Shuhei Nomura, Shinji Arai, Kaoruko Torii, Kentaro Kurata, Miho Sato, Shuichi Shimakawa, Noriyuki Azuma, Tsutomu Ogata, Yoshinao Wada, Nobuhiko Okamoto, Hirotomo Saitsu, Sachiko Nishina and Yoshihiro Hotta

Genes 2022, 13(2), 359; https://doi.org/10.3390/genes13020359 - 16 Feb 2022

Cited by 4 | Viewed by 2369

Abstract

Purpose: Uniparental disomy (UPD) is a rare chromosomal abnormality. We performed whole-exosome sequencing (WES) in cases of early-onset retinal dystrophy and identified two cases likely caused by UPD. Herein, we report these two cases and attempt to clarify the clinical picture of retinal [...] Read more.

Purpose: Uniparental disomy (UPD) is a rare chromosomal abnormality. We performed whole-exosome sequencing (WES) in cases of early-onset retinal dystrophy and identified two cases likely caused by UPD. Herein, we report these two cases and attempt to clarify the clinical picture of retinal dystrophies caused by UPD. Methods: WES analysis was performed for two patients and their parents, who were not consanguineous. Functional analysis was performed in cases suspected of congenital disorders of glycosylation (CDG). We obtained clinical case data and reviewed the literature. Results: In case 1, a novel c.57G>C, p.(Trp19Cys) variant in SRD5A3 was detected homozygously. Genetic analysis suggested a maternal UPD on chromosome 4, and functional analysis confirmed CDG. Clinical findings showed early-onset retinal dystrophy, intellectual disability, and epilepsy. In case 2, an Alu insertion (c.4052_4053ins328, p.[Tyr1352Alafs]) in RP1 was detected homozygously. Maternal UPD on chromosome 8 was suspected. The clinical picture was consistent with RP1-related retinitis pigmentosa. Although the clinical features of retinal dystrophy by UPD may vary, most cases present with childhood onset. Conclusions: There have been limited reports of retinal dystrophy caused by UPD, suggesting that it is rare. Genetic counseling may be encouraged in pediatric cases of retinal dystrophy. Full article

(This article belongs to the Special Issue Study of Inherited Retinal Diseases)

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19 pages, 3329 KiB

Open AccessArticle

Precision Medicine through Next-Generation Sequencing in Inherited Eye Diseases in a Korean Cohort

by Dabin Moon, Hye Won Park, Dongheon Surl, Dongju Won, Seung-Tae Lee, Saeam Shin, Jong Rak Choi and Jinu Han

Genes 2022, 13(1), 27; https://doi.org/10.3390/genes13010027 - 23 Dec 2021

Cited by 11 | Viewed by 3603

Abstract

In this study, we investigated medically or surgically actionable genes in inherited eye disease, based on clinical phenotype and genomic data. This retrospective consecutive case series included 149 patients with inherited eye diseases, seen by a single pediatric ophthalmologist, who underwent genetic testing [...] Read more.

In this study, we investigated medically or surgically actionable genes in inherited eye disease, based on clinical phenotype and genomic data. This retrospective consecutive case series included 149 patients with inherited eye diseases, seen by a single pediatric ophthalmologist, who underwent genetic testing between 1 March 2017 and 28 February 2018. Variants were detected using a target enrichment panel of 429 genes and known deep intronic variants associated with inherited eye disease. Among 149 patients, 38 (25.5%) had a family history, and this cohort includes heterogeneous phenotype including anterior segment dysgenesis, congenital cataract, infantile nystagmus syndrome, optic atrophy, and retinal dystrophy. Overall, 90 patients (60.4%) received a definite molecular diagnosis. Overall, NGS-guided precision care was provided to 8 patients (5.4%). The precision care included cryotherapy to prevent retinal detachment in COL2A1 Stickler syndrome, osteoporosis management in patients with LRP5-associated familial exudative vitreoretinopathy, and avoidance of unnecessary phlebotomy in hyperferritinemia-cataract syndrome. A revision of the initial clinical diagnosis was made in 22 patients (14.8%). Unexpected multi-gene deletions and dual diagnosis were noted in 4 patients (2.7%). We found that precision medical or surgical managements were provided for 8 of 149 patients (5.4%), and multiple locus variants were found in 2.7% of cases. These findings are important because individualized management of inherited eye diseases can be achieved through genetic testing. Full article

(This article belongs to the Special Issue Study of Inherited Retinal Diseases)

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11 pages, 2128 KiB

Open AccessArticle

Genetic Characteristics and Phenotype of Korean Patients with Stickler Syndrome: A Korean Multicenter Analysis Report No. 1

by Soon-Il Choi, Se-Joon Woo, Baek-Lok Oh, Jinu Han, Hyun-Taek Lim, Byung-Joo Lee, Kwangsic Joo, Jun-Young Park, Ja-Hyun Jang, Min-Kyung So and Sang-Jin Kim

Genes 2021, 12(10), 1578; https://doi.org/10.3390/genes12101578 - 05 Oct 2021

Cited by 4 | Viewed by 2028

Abstract

Stickler syndrome is an inherited connective tissue disorder of collagen. There are relatively few reports of East Asian patients, and no large-scale studies have been conducted in Korean patients yet. In this study, we retrospectively analyzed the genetic characteristics and clinical features of [...] Read more.

Stickler syndrome is an inherited connective tissue disorder of collagen. There are relatively few reports of East Asian patients, and no large-scale studies have been conducted in Korean patients yet. In this study, we retrospectively analyzed the genetic characteristics and clinical features of Korean Stickler syndrome patients. Among 37 genetically confirmed Stickler syndrome patients, 21 types of gene variants were identified, of which 12 were novel variants. A total of 30 people had variants in the COL2A1 gene and 7 had variants in the COL11A1 gene. Among the types of pathogenic variants, missense variants were found in 11, nonsense variants in 8, and splice site variants in 7. Splicing variants were frequently associated with retinal detachment (71%) followed by missense variants. This is the first large-scale study of Koreans with Stickler syndrome, which will expand the spectrum of genetic variations of Stickler syndrome. Full article

(This article belongs to the Special Issue Study of Inherited Retinal Diseases)

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11 pages, 924 KiB

Open AccessArticle

Clinical Characterization of Korean Patients with Pseudoxanthoma Elasticum and Angioid Streaks

by Ki Won Jin, Kwangsic Joo and Se Joon Woo

Genes 2021, 12(8), 1207; https://doi.org/10.3390/genes12081207 - 04 Aug 2021

Cited by 3 | Viewed by 2056

Abstract

This study aimed to characterize Korean patients with pseudoxanthoma elasticum (PXE) presenting with angioid streaks. Retinal phenotypes were longitudinally evaluated by multimodal ophthalmic imaging, and targeted gene panel sequencing for inherited retinal diseases was conducted. Seven subjects from unrelated families (median age, 51.2 [...] Read more.

This study aimed to characterize Korean patients with pseudoxanthoma elasticum (PXE) presenting with angioid streaks. Retinal phenotypes were longitudinally evaluated by multimodal ophthalmic imaging, and targeted gene panel sequencing for inherited retinal diseases was conducted. Seven subjects from unrelated families (median age, 51.2 years) were enrolled and followed for a median of 3.2 years. Four asymptomatic patients were significantly younger than three symptomatic patients with decreased visual acuity at presentation (mean age; 38.1 vs. 61.5 years, p = 0.020). The asymptomatic patients maintained good vision (20/32 or better) and had no choroidal neovascularization (CNV) over the observation period. The symptomatic patients showed additional reduction in visual acuity and bilateral CNV occurrence during the longitudinal follow-up. Pathogenic ABCC6 variants were identified in all patients, leading to a diagnosis of PXE. Heterozygous monoallelic variants were identified in four patients and compound heterozygous variants were detected in three patients. Nine ABCC6 variants were identified, including one novel variant, c.2035G>T [p.Glu679Ter]. This is the first genetic study of Korean patients with PXE. Full article

(This article belongs to the Special Issue Study of Inherited Retinal Diseases)

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14 pages, 29477 KiB

Open AccessArticle

Clinical and Genetic Characteristics of Korean Congenital Stationary Night Blindness Patients

by Hyeong-Min Kim, Kwangsic Joo, Jinu Han and Se-Joon Woo

Genes 2021, 12(6), 789; https://doi.org/10.3390/genes12060789 - 21 May 2021

Cited by 14 | Viewed by 2909

Abstract

In this study, we investigated the clinical and genetic characteristics of 19 Korean patients with congenital stationary night blindness (CSNB) at two tertiary hospitals. Clinical evaluations, including fundus photography, spectral-domain optical coherence tomography, and electroretinography, were performed. Genetic analyses were conducted using targeted [...] Read more.

In this study, we investigated the clinical and genetic characteristics of 19 Korean patients with congenital stationary night blindness (CSNB) at two tertiary hospitals. Clinical evaluations, including fundus photography, spectral-domain optical coherence tomography, and electroretinography, were performed. Genetic analyses were conducted using targeted panel sequencing or whole exome sequencing. The median age was 5 (3–21) years at the initial examination, 2 (1–8) years at symptom onset, and 11 (5–28) years during the final visit. Genetic mutations were identified as CNGB1 and GNAT1 for the Riggs type (n = 2), TRPM1 and NYX for the complete type (n = 3), and CACNA1F (n = 14) for the incomplete type. Ten novel variants were identified, and best-corrected visual acuity (BCVA) and spherical equivalents (SE) were related to each type of CSNB. The Riggs and TRPM1 complete types presented mild myopia and good BCVA without strabismus and nystagmus, whereas the NYX complete and incomplete types showed mixed SE and poor BCVA with strabismus and nystagmus. This is the first case series of Korean patients with CSNB, and further studies with a larger number of subjects should be conducted to correlate the clinical and genetic aspects of CSNB. Full article

(This article belongs to the Special Issue Study of Inherited Retinal Diseases)

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13 pages, 1658 KiB

Open AccessArticle

Diverse Genetic Landscape of Suspected Retinitis Pigmentosa in a Large Korean Cohort

by Yoon-Jeon Kim, You-Na Kim, Young-Hee Yoon, Eul-Ju Seo, Go-Hun Seo, Changwon Keum, Beom-Hee Lee and Joo-Yong Lee

Genes 2021, 12(5), 675; https://doi.org/10.3390/genes12050675 - 30 Apr 2021

Cited by 10 | Viewed by 3234

Abstract

We conducted targeted next-generation sequencing (TGS) and/or whole exome sequencing (WES) to assess the genetic profiles of clinically suspected retinitis pigmentosa (RP) in the Korean population. A cohort of 279 unrelated Korean patients with clinically diagnosed RP and available family members underwent molecular [...] Read more.

We conducted targeted next-generation sequencing (TGS) and/or whole exome sequencing (WES) to assess the genetic profiles of clinically suspected retinitis pigmentosa (RP) in the Korean population. A cohort of 279 unrelated Korean patients with clinically diagnosed RP and available family members underwent molecular analyses using TGS consisting of 88 RP-causing genes and/or WES with clinical variant interpretation. The combined genetic tests (TGS and/or WES) found a mutation in the 44 RP-causing genes and seven inherited retinal disease (IRD)-causing genes, and the total mutation detection rate was 57%. The mutation detection rate was higher in patients who experienced visual deterioration at a younger age (75.4%, age of symptom onset under 10 years) and who had a family history of RP (70.7%). The most common causative genes were EYS (8.2%), USH2A (6.8%), and PDE6B (4.7%), but mutations were dispersed among the 51 RP/IRD genes generally. Meanwhile, the PDE6B mutation was the most common in patients experiencing initial symptoms in their first decade, EYS in their second to third decades, and USH2A in their fifth decades and older. Of note, WES revealed some unexpected genotypes: ABCC6, CHM, CYP4V2, RS1, TGFBI, VPS13B, and WDR19, which were verified by ophthalmological re-phenotyping. Full article

(This article belongs to the Special Issue Study of Inherited Retinal Diseases)

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12 pages, 3407 KiB

Open AccessArticle

Autosomal Recessive Retinitis Pigmentosa Associated with Three Novel REEP6 Variants in Chinese Population

by Lujia Zhang, Ya Li, Litao Qin, Yu Wu and Bo Lei

Genes 2021, 12(4), 537; https://doi.org/10.3390/genes12040537 - 07 Apr 2021

Cited by 8 | Viewed by 2418

Abstract

Retinitis pigmentosa 77 is caused by mutations of REEP6 (MIM: 609346), which encodes a protein for the development of photoreceptors. Our study was to identify disease-causing variants in three Chinese families using targeted next-generation sequencing (NGS). Multiple lines of computational predictions combined with [...] Read more.

Retinitis pigmentosa 77 is caused by mutations of REEP6 (MIM: 609346), which encodes a protein for the development of photoreceptors. Our study was to identify disease-causing variants in three Chinese families using targeted next-generation sequencing (NGS). Multiple lines of computational predictions combined with in vitro cellular experiments were applied to evaluate the pathogenicity of the newly found variants. Three novel variants in REEP6, including one missense variant, c.268G>C, one frameshift variant, c.468delC, and one splicing variant, c.598+1G>C, were found, while c.268G>C was detected in all probands. The three variants were classified as likely pathogenic by the American College of Medical Genetics and Genomics (ACMG). REEP6 variant proteins c.268G>C and c.468delC in cultured cells destabilized the REEP6 protein and induced intracellular inclusions. Our data suggested that REEP6 c.268G>C may be a recurrent causative variant in Chinese autosomal recessive retinitis pigmentosa patients. Full article

(This article belongs to the Special Issue Study of Inherited Retinal Diseases)

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17 pages, 1635 KiB

Open AccessArticle

Retinal Oxygenation in Inherited Diseases of the Retina

by Cengiz Türksever, Lisette T. López Torres, Christophe Valmaggia and Margarita G. Todorova

Genes 2021, 12(2), 272; https://doi.org/10.3390/genes12020272 - 14 Feb 2021

Cited by 5 | Viewed by 1947

Abstract

(1) Background: The aim of our study was to investigate the relationship between retinal metabolic alterations (retinal vessel oximetry, RO) and structural findings (retinal vessel diameter, central retinal thickness and retinal nerve fiber layer thickness, RNFL) in patients with inherited retinal diseases (IRDs). [...] Read more.

(1) Background: The aim of our study was to investigate the relationship between retinal metabolic alterations (retinal vessel oximetry, RO) and structural findings (retinal vessel diameter, central retinal thickness and retinal nerve fiber layer thickness, RNFL) in patients with inherited retinal diseases (IRDs). (2) Methods: A total of 181 eyes of 92 subjects were examined: 121 eyes of 62 patients with IRDs were compared to 60 eyes of 30 healthy age-matched controls. The retinal vessel oximetry was performed with the oxygen saturation measurement tool of the Retinal Vessel Analyser (RVA; IMEDOS Systems UG, Jena, Germany). The oxygen saturation in all four major peripapillary retinal arterioles (A-SO₂; %) and venules (V-SO₂; %) were measured and their difference (A-V SO₂; %) was calculated. Additionally, retinal vessel diameters of the corresponding arterioles (D-A; µm) and venules (D-V; µm) were determined. The peripapillary central retinal thickness and the RNFL thickness were measured using spectral domain optical coherence tomography (SD-OCT) (Carl Zeiss Meditec, Dublin, CA, USA). Moreover, we calculated the mean central retinal oxygen exposure (cO₂-E; %/µm) and the mean peripapillary oxygen exposure (pO₂-E; %/µm) per micron of central retinal thickness and nerve fiber layer thickness by dividing the mean central retinal thickness (CRT) and the RNFL thickness with the mean A-V SO₂. (3) Results: Rod-cone dystrophy patients had the highest V-SO₂ and A-SO₂, the lowest A-V SO₂, the narrowest D-A and D-V and the thickest RNFL, when compared not only to controls (p ≤ 0.040), but also to patients with other IRDs. Furthermore, in rod-cone dystrophies the cO₂-E and the pO₂-E were higher in comparison to controls and to patients with other IRDs (p ≤ 0.005). Cone-rod dystrophy patients had the lowest cO₂-E compared to controls and patients with other IRDs (p ≤ 0.035). Evaluated in central zones, the cO₂-E was significantly different when comparing cone-rod dystrophy (CRD) against rod-cone dystrophy (RCD) patients in all zones (p < 0.001), whereas compared with controls and patients with inherited macular dystrophy this was observed only in zones 1 and 2 (p ≤ 0.018). The oxygen exposure was also the highest in the RCD group for both the nasal and the temporal peripapillary area, among all the evaluated groups (p ≤ 0.025). (4) Conclusions: The presented metabolic-structural approach enhances our understanding of inherited photoreceptor degenerations. Clearly demonstrated through the O₂-E comparisons, the central and the peripapillary retina in rod-cone dystrophy eyes consume less oxygen than the control-eyes and eyes with other IRDs. Rod-cone dystrophy eyes seem to be proportionally more exposed to oxygen, the later presumably leading to more pronounced oxidative damage-related remodeling. Full article

(This article belongs to the Special Issue Study of Inherited Retinal Diseases)

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Review

Jump to: Research, Other

20 pages, 314 KiB

Open AccessReview

Developing Non-Human Primate Models of Inherited Retinal Diseases

by Ivan Seah, Debbie Goh, Hwei Wuen Chan and Xinyi Su

Genes 2022, 13(2), 344; https://doi.org/10.3390/genes13020344 - 14 Feb 2022

Cited by 2 | Viewed by 2608

Abstract

Inherited retinal diseases (IRDs) represent a genetically and clinically heterogenous group of diseases that can eventually lead to blindness. Advances in sequencing technologies have resulted in better molecular characterization and genotype–phenotype correlation of IRDs. This has fueled research into therapeutic development over the [...] Read more.

Inherited retinal diseases (IRDs) represent a genetically and clinically heterogenous group of diseases that can eventually lead to blindness. Advances in sequencing technologies have resulted in better molecular characterization and genotype–phenotype correlation of IRDs. This has fueled research into therapeutic development over the recent years. Animal models are required for pre-clinical efficacy assessment. Non-human primates (NHP) are ideal due to the anatomical and genetic similarities shared with humans. However, developing NHP disease to recapitulate the disease phenotype for specific IRDs may be challenging from both technical and cost perspectives. This review discusses the currently available NHP IRD models and the methods used for development, with a particular focus on gene-editing technologies. Full article

(This article belongs to the Special Issue Study of Inherited Retinal Diseases)

Other

Jump to: Research, Review

8 pages, 1150 KiB

Open AccessCase Report

Expanding the Phenotypic and Genotypic Spectrum of Bietti Crystalline Dystrophy

by Mariana Matioli da Palma, Fabiana Louise Motta, Mariana Vallim Salles, Caio Henrique Marques Texeira, André V. Gomes, Ricardo Casaroli-Marano and Juliana Maria Ferraz Sallum

Genes 2021, 12(5), 713; https://doi.org/10.3390/genes12050713 - 10 May 2021

Cited by 7 | Viewed by 2533

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Study of Inherited Retinal Diseases)

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7 pages, 1381 KiB

Open AccessCase Report

TUBB3 M323V Syndrome Presents with Infantile Nystagmus

by Soohwa Jin, Sung-Eun Park, Dongju Won, Seung-Tae Lee, Sueng-Han Han and Jinu Han

Genes 2021, 12(4), 575; https://doi.org/10.3390/genes12040575 - 15 Apr 2021

Cited by 8 | Viewed by 2280

Abstract

Variants in the TUBB3 gene, one of the tubulin-encoding genes, are known to cause congenital fibrosis of the extraocular muscles type 3 and/or malformations of cortical development. Herein, we report a case of a 6-month-old infant with c.967A>G:p.(M323V) variant in the TUBB3 gene, [...] Read more.

Variants in the TUBB3 gene, one of the tubulin-encoding genes, are known to cause congenital fibrosis of the extraocular muscles type 3 and/or malformations of cortical development. Herein, we report a case of a 6-month-old infant with c.967A>G:p.(M323V) variant in the TUBB3 gene, who had only infantile nystagmus without other ophthalmological abnormalities. Subsequent brain magnetic resonance imaging (MRI) revealed cortical dysplasia. Neurological examinations did not reveal gross or fine motor delay, which are inconsistent with the clinical characteristics of patients with the M323V syndrome reported so far. A protein modeling showed that the M323V mutation in the TUBB3 gene interferes with αβ heterodimer formation with the TUBA1A gene. This report emphasizes the importance of considering TUBB3 and TUBA1A tubulinopathy in infantile nystagmus. A brain MRI should also be considered for these patients, although in the absence of other neurologic signs or symptoms. Full article

(This article belongs to the Special Issue Study of Inherited Retinal Diseases)

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8 pages, 5678 KiB

Open AccessCase Report

Long-Term Follow-Up of Peripheral Pigmentary Retinopathy in Asian Patients with Danon Disease

by Jee Myung Yang, Beom Hee Lee, Gi-Byoung Nam, June-Gone Kim and Joo Yong Lee

Genes 2020, 11(11), 1356; https://doi.org/10.3390/genes11111356 - 16 Nov 2020

Cited by 1 | Viewed by 2104

Abstract

Background: Peripheral pigmentary changes are common amongst women with Danon disease; however, there is currently a lack of longitudinal observational studies of the retinal changes in this condition, and the long-term visual prognosis is not well understood. Methods and Results: In this report, [...] Read more.

Background: Peripheral pigmentary changes are common amongst women with Danon disease; however, there is currently a lack of longitudinal observational studies of the retinal changes in this condition, and the long-term visual prognosis is not well understood. Methods and Results: In this report, we present long-term follow-up data (12 years of follow-up) regarding peripheral retinopathy in an Asian woman and her mother who were both diagnosed with Danon disease. Both patients showed a novel nonsense mutation of the LAMP2 gene (c.123 of exon 2). During the follow-up period, no evident extension of peripheral pigmented lesions or visual field progression was observed. Conclusions: We report, for the first time, the long-term longitudinal follow-up of Danon disease-related retinopathy in an Asian patient featuring an indolent macular-sparing peripheral lesion. Full article

(This article belongs to the Special Issue Study of Inherited Retinal Diseases)

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