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

2018 ◽  
Vol 102 (10) ◽  
pp. 1378-1386 ◽  
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.

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

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.

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

Genes ◽  
2021 ◽  
Vol 12 (11) ◽  
pp. 1824
Author(s):  
Cristina Villanueva-Mendoza ◽  
Miquel Tuson ◽  
David Apam-Garduño ◽  
Marta de Castro-Miró ◽  
Raul Tonda ◽  
...  
Keyword(s):  
Diagnostic Yield ◽  
Novel Mutation ◽  
Genetic Diagnosis ◽  
Inherited Retinal Dystrophies ◽  
Pathogenic Variants ◽  
Retinal Dystrophies ◽  
Whole Exome ◽  
Genetic Landscape ◽  
Genetic Features ◽  
Gene Panels

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.

scholarly journals Genotypes Predispose Phenotypes—Clinical Features and Genetic Spectrum of ABCA4-Associated Retinal Dystrophies

Genes ◽  
2020 ◽  
Vol 11 (12) ◽  
pp. 1421
Author(s):  
Yu-Chi Sung ◽  
Chang-Hao Yang ◽  
Chung-May Yang ◽  
Chao-Wen Lin ◽  
Ding-Siang Huang ◽  
...  
Keyword(s):  
Visual Acuity ◽  
Retinal Degeneration ◽  
Medical Center ◽  
Fundus Autofluorescence ◽  
Genetic Diagnosis ◽  
Common Disease ◽  
Genetic Characteristics ◽  
Retinal Dystrophies ◽  
High Prevalence ◽  
Abca4 Gene

The ABCA4 gene is one of the most common disease-causing genes of inherited retinal degeneration. In this study, we report different phenotypes of ABCA4-associated retinal dystrophies in the Taiwanese population, its clinical progression, and its relationship with genetic characteristics. Thirty-seven subjects were recruited and all patients underwent serial ophthalmic examinations at a single medical center. Fundus autofluorescence (FAF) images were quantified for clinical evaluation, and panel-based next-generation sequencing testing was performed for genetic diagnosis. Visual preservation, disease progression, and genotype–phenotype correlation were analyzed. In this cohort, ABCA4-associated retinal degeneration presented as Stargardt disease 1 (STGD1, 62.16%), retinitis pigmentosa (32.43%), and cone-rod dystrophy (5.41%). STGD1 could be further divided into central and dispersed types. In each phenotype, the lesion areas quantified by FAF increased with age (p < 0.01) and correlated with poorer visual acuity. However, three patients had the foveal sparing phenotype and had relatively preserved visual acuity. Forty-two ABCA4 variants were identified as disease-causing, with c.1804C>T (p.Arg602Trp) the most frequent (37.84%). Patients with a combination of severe/null variants could have more extensive phenotypes, such as arRP and dispersed STGD1. This is the first cohort study of ABCA4-associated retinal degeneration in Taiwan with wide spectrums of both genotypic and phenotypic characteristics. An extremely high prevalence of c.1804C>T, which has not been reported in East Asia before, was noted. The extensiveness of retinal involvement might be regarded as a spectrum of ABCA4-associated retinal dystrophies. Different types of genetic variations could lead to distinctive phenotypes, according to the coding impact of variants.

Identification of Two Novel Mutations in PKHD1 Gene from Two Families with Polycystic Kidney Disease by Whole Exome Sequencing

2021 ◽  
Vol 22 ◽  
Author(s):  
Masoud Heidari ◽  
Hamid Gharshasbi ◽  
Alireza Isazadeh ◽  
Morteza Soleyman-Nejad ◽  
Mohammad Hossein Taskhiri ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Exome Sequencing ◽  
Polycystic Kidney Disease ◽  
Whole Exome Sequencing ◽  
Novel Mutation ◽  
Genetic Diagnosis ◽  
Genetic Alterations ◽  
Polycystic Kidney ◽  
Novel Mutations ◽  
Whole Exome

Background:: Polycystic kidney disease (PKD) is an autosomal recessive disorder resulting from mutations in the PKHD1 gene on chromosome 6 (6p12), a large gene spanning 470 kb of genomic DNA. Objective: The aim of the present study was to report newly identified mutations in the PKHD1 gene in two Iranian families with PKD. Materials and Methods: Genetic alterations of a 3-month-old boy and a 27-year-old girl with PKD were evaluated using whole-exome sequencing. The PCR direct sequencing was performed to analyse the co-segregation of the variants with the disease in the family. Finally, the molecular function of the identified novel mutations was evaluated by in silico study. Results: In the 3 month-old boy, a novel homozygous frameshift mutation was detected in the PKHD1 gene, which can cause PKD. Moreover, we identified three novel heterozygous missense mutations in ATIC, VPS13B, and TP53RK genes. In the 27-year-old woman, with two recurrent abortions history and two infant mortalities at early weeks due to metabolic and/or renal disease, we detected a novel missense mutation on PKHD1 gene and a novel mutation in ETFDH gene. Conclusion: In general, we have identified two novel mutations in the PKHD1 gene. These molecular findings can help accurately correlate genotype and phenotype in families with such disease in order to reduce patient births through preoperative genetic diagnosis or better management of disorders.

scholarly journals Multimodal imaging of hereditary retinal dystrophies (a series of clinical cases)

2020 ◽  
Vol 13 (4) ◽  
pp. 75-82
Author(s):  
S. V. Milash ◽  
I. V. Zolnikova ◽  
V. V. Kadyshev
Keyword(s):  
Multimodal Imaging ◽  
Fundus Autofluorescence ◽  
Diagnostic Methods ◽  
Science System ◽  
Non Invasive ◽  
Retinal Dystrophies ◽  
Fundus Imaging ◽  
Inherited Retinal Degeneration ◽  
Fundus Flavimaculatus ◽  
Clinical Cases

Multimodal visualization data of inherited retinal degeneration (IRD) on a Mirante platform (Nidek, Japan), used in a number of clinical cases, is compared with the data obtained by electrophysiological diagnostic methods. 4 patients with varying IRD were examined: adult-onset foveomacular vitelliform dystrophy, Stargardt disease, including those with fundus flavimaculatus, and retinitis pigmentosa. Multimodal imaging includes: colour fundus imaging, fundus autofluorescence, retro mode, and optical coherence tomography. Electroretinography was performed using an MBN electroretinograph (Russia), and electrooculography was performed using a RETIscan Science system (Roland Consult, Germany). Using non-invasive retinal imaging methods, specific patterns of inherited dystrophies were shown, which correlated well with the data of electrophysiological research methods. The combination of multimodal imaging on the Mirante platform (Nidek, Japan) in combination with electrophysiological diagnostic methods can be successfully used in complex diagnostics, monitoring of the progression, and evaluation of the results of IRD treatment.

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

Circulation ◽  
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.

Exome Sequencing Identifies a Novel DES Mutation (R227C) in a Chinese Dilated Cardiomyopathy Family

Cardiology ◽  
2017 ◽  
Vol 137 (2) ◽  
pp. 78-82 ◽  
Author(s):  
Rong Yu ◽  
Lv Liu ◽  
Chan Chen ◽  
Jin-Mei Shen
Keyword(s):  
Dilated Cardiomyopathy ◽  
Exome Sequencing ◽  
Genetic Factors ◽  
Novel Mutation ◽  
Genetic Diagnosis ◽  
Chinese Family ◽  
Common Disease ◽  
Disease Genes ◽  
Whole Exome ◽  
Gene Filtering

Objectives: Dilated cardiomyopathy (DCM) is a common disease in the clinic, and it is the leading cause of heart failure and sudden cardiac death. Previous studies have proven that genetic factors play a crucial role in the occurrence of DCM; more than 50 disease genes including desmin (DES) have been identified to be associated with DCM. At present, most DES mutations are reported in desmin-related myofibrilla myopathy patients, but variants leading to isolated DCM are rarely reported. Methods: We applied whole-exome sequencing and cardiomyopathy-related gene filtering strategies to discover the genetic factors in a Chinese DCM family. Results: A novel mutation (c.679 C>T /p.R227C) in exon 3 of DES was identified and cosegregated with the affected members of a Chinese family with isolated DCM phenotypes (left ventricle and left atrial diameters). Conclusion: This mutation leads to a substitution of arginine by cysteine and it is predicted to be deleterious by bioinformatics programs. Our study not only contributes to the genetic diagnosis and counseling of families with DCM, but it also further proves that DES mutations may lead to isolated DCM and provides a new case for the study of the relationship between DES mutations and DCM.

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

2017 ◽  
Vol 7 (1) ◽  
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

scholarly journals High-Throughput Sequencing to Identify Mutations Associated with Retinal Dystrophies

Genes ◽  
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.

scholarly journals A Novel Non-frameshift ADA Deletion Detected by Whole Exome Sequencing in an Iranian Family with Severe Combined Immunodeficiency

2020 ◽  
Author(s):  
Taravat Talebi ◽  
Alirezai Biglari ◽  
Mohammad Shahroeei ◽  
Majid Changi-Ashtiani ◽  
Hossein Dinmohammadi ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Novel Mutation ◽  
Genetic Disorders ◽  
Severe Combined Immunodeficiency ◽  
Genetic Diagnosis ◽  
Sample Volume ◽  
Combined Immunodeficiency ◽  
Whole Exome ◽  
And Function

Severe combined immunodeficiency (SCID) comprises a heterogeneous group of genetic disorders caused by early defects in the development and function of T cells. Other lymphocyte lineages (B and/or natural killer cells) are variably affected. With a worldwide frequency of approximately 1:50,000 live births, SCID may result from diverse mutations in over 16 genes. Whole-exome sequencing (WES) provides an opportunity for parallel screening of all those genes. This approach is also useful for genetic diagnosis in parents whose infant expired before genetic testing. Here, we describe a heterozygous novel non-frameshift deletion (c.587_598del p.196_199del) in the adenosine deaminase (ADA) gene identified by WES in healthy parents of an expired child with SCID. The mutation was subsequently confirmed to be homozygous in the deceased baby whose left-over blood sample volume was insufficient for direct WES analysis. In conclusion, we here describe a novel mutation in ADA, a well-known SCID gene.  

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