The Genetic Landscape of Inherited Retinal Diseases in a Mexican Cohort: Genes, Mutations and Phenotypes

In this work, we aimed to provide the genetic diagnosis of a large cohort of patients affected with inherited retinal dystrophies (IRDs) from Mexico. Our data add valuable information to the genetic portrait in rare ocular diseases of Mesoamerican populations, which are mostly under-represented in genetic studies. A cohort of 144 unrelated probands with a clinical diagnosis of IRD were analyzed by next-generation sequencing using target gene panels (overall including 346 genes and 65 intronic sequences). Four unsolved cases were analyzed by whole-exome sequencing (WES). The pathogenicity of new variants was assessed by in silico prediction algorithms and classified following the American College of Medical Genetics and Genomics (ACMG) guidelines. Pathogenic or likely pathogenic variants were identified in 105 probands, with a final diagnostic yield of 72.9%; 17 cases (11.8%) were partially solved. Eighteen patients were clinically reclassified after a genetic diagnostic test (17.1%). In our Mexican cohort, mutations in 48 genes were found, with ABCA4, CRB1, RPGR and USH2A as the major contributors. Notably, over 50 new putatively pathogenic variants were identified. Our data highlight cases with relevant clinical and genetic features due to mutations in the RAB28 and CWC27 genes, enrich the novel mutation repertoire and expand the IRD landscape of the Mexican population.

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Updating the Genetic Landscape of Inherited Retinal Dystrophies

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.645600 ◽

2021 ◽

Vol 9 ◽

Author(s):

Belén García Bohórquez ◽

Elena Aller ◽

Ana Rodríguez Muñoz ◽

Teresa Jaijo ◽

Gema García García ◽

...

Keyword(s):

Genetic Diagnosis ◽

Diagnostic Process ◽

Reproductive Decisions ◽

Inherited Retinal Dystrophies ◽

Pathogenic Variants ◽

Retinal Dystrophies ◽

Genetic Landscape ◽

Custom Panel ◽

Generation Sequencing ◽

Autosomal Recessive Pattern

Inherited retinal dystrophies (IRD) are a group of diseases characterized by the loss or dysfunction of photoreceptors and a high genetic and clinical heterogeneity. Currently, over 270 genes have been associated with IRD which makes genetic diagnosis very difficult. The recent advent of next generation sequencing has greatly facilitated the diagnostic process, enabling to provide the patients with accurate genetic counseling in some cases. We studied 92 patients who were clinically diagnosed with IRD with two different custom panels. In total, we resolved 53 patients (57.6%); in 12 patients (13%), we found only one mutation in a gene with a known autosomal recessive pattern of inheritance; and 27 patients (29.3%) remained unsolved. We identified 120 pathogenic or likely pathogenic variants; 30 of them were novel. Among the cone-rod dystrophy patients, ABCA4 was the most common mutated gene, meanwhile, USH2A was the most prevalent among the retinitis pigmentosa patients. Interestingly, 10 families carried pathogenic variants in more than one IRD gene, and we identified two deep-intronic variants previously described as pathogenic in ABCA4 and CEP290. In conclusion, the IRD study through custom panel sequencing demonstrates its efficacy for genetic diagnosis, as well as the importance of including deep-intronic regions in their design. This genetic diagnosis will allow patients to make accurate reproductive decisions, enroll in gene-based clinical trials, and benefit from future gene-based treatments.

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Genetic landscape of 6089 inherited retinal dystrophies affected cases in Spain and their therapeutic and extended epidemiological implications

Scientific Reports ◽

10.1038/s41598-021-81093-y ◽

2021 ◽

Vol 11 (1) ◽

Cited By ~ 4

Author(s):

Irene Perea-Romero ◽

◽

Gema Gordo ◽

Ionut F. Iancu ◽

Marta Del Pozo-Valero ◽

...

Keyword(s):

Genetic Diagnosis ◽

Cross Sectional Study ◽

Molecular Techniques ◽

Cross Sectional ◽

Autonomous Communities ◽

Inherited Retinal Dystrophies ◽

Pathogenic Variants ◽

Retinal Dystrophies ◽

Family Pedigree ◽

Genetic Landscape

AbstractInherited 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.

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Identification of a novel RPGR mutation associated with X-linked cone-rod dystrophy in a Chinese family

BMC Ophthalmology ◽

10.1186/s12886-021-02166-0 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Yafang Wang ◽

Shu Liu ◽

Yuanqi Zhai ◽

Yang Liu ◽

Xiaoling Wan ◽

...

Keyword(s):

Novel Mutation ◽

Genetic Diagnosis ◽

Chinese Family ◽

Central Visual Field ◽

Mammalian Expression ◽

Inherited Retinal Dystrophies ◽

Retinal Dystrophies ◽

Whole Exome ◽

Vision Defects ◽

Female Carriers

Abstract Background Cone-rod dystrophy (CORD) is a group of inherited retinal dystrophies, characterized by decreased visual acuity, color vision defects, photophobia, and decreased sensitivity in the central visual field. Our study has identified a novel pathogenic variant associated with X-linked cone-rod dystrophy (XLCORD) in a Chinese family. Methods All six family members, including the proband, affected siblings, cousins and female carriers, have underwent thorough ophthalmic examinations. The whole exome sequencing was performed for the proband, followed by Sanger sequencing for spilt-sample validation. A mammalian expression vector (AAV-MCS) with mutated retinitis pigmentosa GTPase regulator (RPGR) sequence was expressed in HEK293 T cells. The mutated protein was verified by Western blotting and immunohistochemistry. Results A novel mutation in the RPGR gene (c.2383G > T, p.E795X) is identified to be responsible for CORD pathogenesis. Conclusions Our findings have expanded the spectrum of CORD-associated mutations in RPGR gene and serve as a basis for genetic diagnosis for X-linked CORD.

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Abstract 11800: Whole Exome Sequencing in a Large Pedigree With DCM Identifies a Novel Mutation in RBM20

Circulation ◽

10.1161/circ.132.suppl_3.11800 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Tomas Robyns ◽

Johan Van Cleemput ◽

Rik Willems ◽

Shalini Jhangiani ◽

Donna Muzny ◽

...

Keyword(s):

Dilated Cardiomyopathy ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Scoring System ◽

Diagnostic Yield ◽

Novel Mutation ◽

Genetic Diagnosis ◽

Single Nucleotide Variants ◽

Large Pedigree ◽

Whole Exome

Background and hypothesis: Familial dilated cardiomyopathy (DCM) is genetically heterogeneous and is associated with mutations in at least 30 different genes. None of these genes have an expected diagnostic yield of more than 10% complicating genetic diagnosis. Whole exome sequencing (WES) is a powerful alternative for the identification of the causal gene, however variant interpretation remains challenging. We performed WES in a large family with autosomal dominant DCM complicated by end stage heart failure and ventricular arrhythmias. The index of this family was evaluated previously by means of targeted gene panel analysis including 28 genes, but no causal mutation was found. Methods and results: WES was applied on 2 affected cousins. First, shared heterozygous variants (single nucleotide variants, small insertions and deletions) located inside the exon or at the exon/intron boundary were selected. Synonymous variants were excluded, except if they were located at the exon/intron boundaries. Variants with a minor allele frequency of >0.1% in publically available exome databases (1000 Genomes and ESP) were excluded. Furthermore, variants that were present in an in-house exome cohort performed for other disease entities were also excluded since these probably represent local SNV’s. The remaining 19 variants were evaluated using a comprehensive scoring system that includes different in-silico analysis tools, orthologous and paralogous conservation and population frequencies. Subsequently Sanger sequencing was performed for 10 variants that were classified as likely pathogenic (N=1) or variants of unknown significance (N=9) according to the scoring system in order to confirm the presence of the variant and to evaluate co-segregation. Only one variant in exon 9 of the RBM20 gene (c.2714T>A, p.Met950Lys, NM_001334363) showed full co-segregation in the 7 affected family members resulting in a maximum 2-point LOD score of 2.1 and suggesting this as the pathogenic mutation responsible for the phenotype. Recently mutations in RBM20 have been linked to dilated cardiomyopathy caused by defective splicing of the giant sarcomeric protein titin. Conclusions: We report the identification of a novel mutation in RBM20 by WES in a large pedigree with DCM.

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Whole exome sequencing and homozygosity mapping reveals genetic defects in consanguineous Iranian families with inherited retinal dystrophies

Scientific Reports ◽

10.1038/s41598-020-75841-9 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Arash Salmaninejad ◽

Nicola Bedoni ◽

Zeinab Ravesh ◽

Mathieu Quinodoz ◽

Nasser Shoeibi ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Snp Array ◽

Homozygosity Mapping ◽

Retinal Cell ◽

Additional Information ◽

Inherited Retinal Dystrophies ◽

Pathogenic Variants ◽

Retinal Dystrophies ◽

Whole Exome

Abstract Inherited retinal dystrophies (IRDs), displaying pronounced genetic and clinical heterogeneity, comprise of a broad range of diseases characterized by progressive retinal cell death and gradual loss of vision. By the combined use of whole exome sequencing (WES), SNP-array and WES-based homozygosity mapping, as well as directed DNA sequencing (Sanger), we have identified nine pathogenic variants in six genes (ABCA4, RPE65, MERTK, USH2A, SPATA7, TULP1) in 10 consanguineous Iranian families. Six of the nine identified variants were novel, including a putative founder mutation in ABCA4 (c.3260A>G, p.Glu1087Gly), detected in two families from Northeastern Iran. Our findings provide additional information to the molecular pathology of IRDs in Iran, hopefully contributing to better genetic counselling and patient management in the respective families from this country.

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B.06 Whole exome sequencing in genetic ataxias associated with cerebellar atrophy: the Canadian experience

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/cjn.2019.95 ◽

2019 ◽

Vol 46 (s1) ◽

pp. S11

Author(s):

L Gauquelin ◽

T Hartley ◽

M Tarnopolsky ◽

DA Dyment ◽

B Brais ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Diagnostic Yield ◽

Genetic Diseases ◽

Genetic Diagnosis ◽

Cerebellar Atrophy ◽

Clinical Findings ◽

Disease Genes ◽

Pathogenic Variants ◽

Whole Exome

Background: Cerebellar atrophy is characterized by loss of cerebellar tissue, with evidence on brain imaging of enlarged interfolial spaces compared to the foliae. Genetic ataxias associated with cerebellar atrophy are a heterogeneous group of disorders. We investigated the prevalence in Canada and the diagnostic yield of whole exome sequencing (WES) for this group of conditions. Methods: Between 2011 and 2017, WES was performed in 91 participants with cerebellar atrophy as part of one of two national research programs, Finding of Rare Genetic Disease Genes (FORGE) or Enhanced Care for Rare Genetic Diseases in Canada (Care4Rare). Results: A genetic diagnosis was established in 58% of cases (53/91). Pathogenic variants were found in 24 known genes, providing a diagnosis for 46/53 participants (87%), and in four novel genes, accounting for 7/53 cases (13%). 38/91 cases (42%) remained unsolved. The most common diagnoses were channelopathies in 12/53 patients (23%) and mitochondrial disorders in 9/53 (17%). Inheritance was autosomal recessive in the majority of cases. Additional clinical findings provided useful clues to some of the diagnoses. Conclusions: This is the first report on the prevalence of genetic ataxias associated with cerebellar atrophy in Canada, and the utility of WES for this group of conditions.

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Whole exome sequencing using Ion Proton system enables reliable genetic diagnosis of inherited retinal dystrophies

Scientific Reports ◽

10.1038/srep42078 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 31

Author(s):

Marina Riera ◽

Rafael Navarro ◽

Sheila Ruiz-Nogales ◽

Pilar Méndez ◽

Anniken Burés-Jelstrup ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Genetic Diagnosis ◽

Inherited Retinal Dystrophies ◽

Retinal Dystrophies ◽

Whole Exome ◽

Ion Proton

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High-Throughput Sequencing to Identify Mutations Associated with Retinal Dystrophies

Genes ◽

10.3390/genes12081269 ◽

2021 ◽

Vol 12 (8) ◽

pp. 1269

Author(s):

Fei Song ◽

Marta Owczarek-Lipska ◽

Tim Ahmels ◽

Marius Book ◽

Sabine Aisenbrey ◽

...

Keyword(s):

High Throughput Sequencing ◽

Genetic Diagnosis ◽

Clinical Manifestations ◽

Sequence Variants ◽

Pathogenic Variants ◽

Retinal Dystrophies ◽

Whole Exome ◽

Uncertain Significance ◽

Disease Associated Genes ◽

Intronic Variants

Retinal dystrophies (RD) are clinically and genetically heterogenous disorders showing mutations in over 270 disease-associated genes. Several millions of people worldwide are affected with different types of RD. Studying the relevance of disease-associated sequence alterations will assist in understanding disorders and may lead to the development of therapeutic approaches. Here, we established a whole exome sequencing (WES) pipeline to rapidly identify disease-associated mutations in patients. Sanger sequencing was applied to identify deep-intronic variants and to verify the co-segregation of WES results within families. We analyzed 26 unrelated patients with different syndromic and non-syndromic clinical manifestations of RD. All patients underwent ophthalmic examinations. We identified nine novel disease-associated sequence variants among 37 variants identified in total. The sequence variants located to 17 different genes. Interestingly, two cases presenting with Stargardt disease carried deep-intronic variants in ABCA4. We have classified 21 variants as pathogenic variants, 4 as benign/likely benign variants, and 12 as variants of uncertain significance. This study highlights the importance of WES-based mutation analyses in RD patients supporting clinical decisions, broadly based genetic diagnosis and support genetic counselling. It is essential for any genetic therapy to expand the mutation spectrum, understand the genes’ function, and correlate phenotypes with genotypes.

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Novel mutation in the choroideremia gene and multi-Mendelian phenotypes in Spanish families

British Journal of Ophthalmology ◽

10.1136/bjophthalmol-2017-311427 ◽

2018 ◽

Vol 102 (10) ◽

pp. 1378-1386 ◽

Cited By ~ 6

Author(s):

Marta de Castro-Miró ◽

Raul Tonda ◽

Gemma Marfany ◽

Ricardo P Casaroli-Marano ◽

Roser Gonzàlez-Duarte

Keyword(s):

Novel Mutation ◽

Imaging Techniques ◽

Fundus Autofluorescence ◽

Genetic Diagnosis ◽

Swept Source ◽

Non Invasive ◽

Efficient Management ◽

Retinal Dystrophies ◽

Whole Exome ◽

Massive Sequencing

AimsWe aimed to accurately diagnose several retinitis pigmentosa (RP) patients with complex ocular phenotypes by combining massive sequencing genetic diagnosis and powerful clinical imaging techniques.MethodsWhole-exome sequencing (WES) of selected patients from two RP families was undertaken. The variants identified were validated by Sanger sequencing and cosegregation analysis. Accurate clinical re-evaluation was performed using electrophysiological and visual field records as well as non-invasive imaging techniques, such as swept-source optical coherence tomography and fundus autofluorescence.ResultsThe WES results highlighted one novel and one reported causative mutations in the X-linked choroideremia gene (CHM), which challenged the initial RP diagnosis. Subsequent clinical re-evaluation confirmed the choroideremia diagnosis. Carrier females showed different degrees of affectation, even between twin sisters, probably due to lyonization. A severe multi-Mendelian phenotype was associated with coincidental dominant pathogenic mutations in two additional genes: PAX6 and PDE6B.ConclusionsGenetic diagnosis via massive sequencing is instrumental in identifying causative mutations in retinal dystrophies and additional genetic variants with an impact on the phenotype. Multi-Mendelian phenotypes previously ascribed to rare syndromes can thus be dissected and molecularly diagnosed. Overall, the combination of powerful genetic diagnosis and clinical non-invasive imaging techniques enables efficient management of patients and their prioritisation for gene-specific therapies.

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Characterization of GUCA1A-associated dominant cone/cone-rod dystrophy: low prevalence among Japanese patients with inherited retinal dystrophies

Scientific Reports ◽

10.1038/s41598-019-52660-1 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 3

Author(s):

Kei Mizobuchi ◽

Takaaki Hayashi ◽

Satoshi Katagiri ◽

Kazutoshi Yoshitake ◽

Kaoru Fujinami ◽

...

Keyword(s):

Japanese Patients ◽

Cone Dystrophy ◽

Progressive Retinal Atrophy ◽

Inherited Retinal Dystrophies ◽

Pathogenic Variants ◽

Japanese Cohort ◽

Whole Exome ◽

Ef Hand ◽

Genetic Features ◽

Low Prevalence

AbstractGUCA1A gene variants are associated with autosomal dominant (AD) cone dystrophy (COD) and cone-rod dystrophy (CORD). GUCA1A-associated AD-COD/CORD has never been reported in the Japanese population. The purpose of this study was to investigate clinical and genetic features of GUCA1A-associated AD-COD/CORD from a large Japanese cohort. We identified 8 variants [c.C50_80del (p.E17VfsX22), c.T124A (p.F42I), c.C204G (p.D68E), c.C238A (p.L80I), c.T295A (p.Y99N), c.A296C (p.Y99S), c.C451T (p.L151F), and c.A551G (p.Q184R)] in 14 families from our whole exome sequencing database composed of 1385 patients with inherited retinal diseases (IRDs) from 1192 families. Three variants (p.Y99N, p.Y99S, and p.L151F), which are located on/around EF-hand domains 3 and 4, were confirmed as “pathogenic”, whereas the other five variants, which did not co-segregate with IRDs, were considered “non-pathogenic”. Ophthalmic findings of 9 patients from 3 families with the pathogenic variants showed central visual impairment from early to middle-age onset and progressive macular atrophy. Electroretinography revealed severely decreased or non-recordable cone responses, whereas rod responses were highly variable, ranging from nearly normal to non-recordable. Our results indicate that the three pathogenic variants, two of which were novel, underlie AD-COD/CORD with progressive retinal atrophy, and the prevalence (0.25%, 3/1192 families) of GUCA1A-associated IRDs may be low among Japanese patients.

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