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.

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

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.

Whole-Exome Sequencing Identifies a Novel Mutation (p.L320R) of Alpha-Actinin 2 in a Chinese Family with Dilated Cardiomyopathy and Ventricular Tachycardia

2019 ◽  
Vol 157 (3) ◽  
pp. 148-152 ◽  
Author(s):  
Liang-Liang Fan ◽  
Hao Huang ◽  
Jie-Yuan Jin ◽  
Jing-Jing Li ◽  
Ya-Qin Chen ◽  
...  
Keyword(s):  
Ventricular Tachycardia ◽  
Dilated Cardiomyopathy ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Novel Mutation ◽  
Genetic Diagnosis ◽  
Pathogenic Mutation ◽  
Left Ventricular ◽  
Chinese Family ◽  
Whole Exome

Dilated cardiomyopathy (DCM) is a severe cardiovascular disease which can lead to heart failure and sudden cardiac death (SCD). The typical feature of DCM is left ventricular enlargement or dilatation. In some conditions, DCM and arrhythmia can occur concurrently, apparently promoting the prevalence of SCD. According to previous studies, mutations in more than 100 genes have been detected in DCM and/or arrhythmia patients. Here, we report a Chinese family with typical DCM, ventricular tachycardia, syncope, and SCD. Using whole-exome sequencing, a novel, likely pathogenic mutation (c.959T>G/p.L320R) of actinin alpha 2 (ACTN2) was identified in all affected family members. This novel mutation was also predicted to be disease-causing by MutationTaster, SIFT, and Polyphen-2. Our study not only expands the spectrum of ACTN2 mutations and contributes to the genetic diagnosis and counseling of the family, but also provides a new case with overlap phenotype that may be caused by the ACTN2 variant.

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 Whole exome sequencing in 17 consanguineous Iranian pedigrees expands the mutational spectrum of inherited retinal dystrophies

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Atta Ur Rehman ◽  
Neda Sepahi ◽  
Nicola Bedoni ◽  
Zeinab Ravesh ◽  
Arash Salmaninejad ◽  
...  
Keyword(s):  
Disease Genes ◽  
Homozygous State ◽  
Traditional Practice ◽  
Genomic Variants ◽  
Mutational Spectrum ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies ◽  
Whole Exome ◽  
Human Disorders ◽  
Generation Sequencing

AbstractInherited retinal dystrophies (IRDs) constitute one of the most heterogeneous groups of Mendelian human disorders. Using autozygome-guided next-generation sequencing methods in 17 consanguineous pedigrees of Iranian descent with isolated or syndromic IRD, we identified 17 distinct genomic variants in 11 previously-reported disease genes. Consistent with a recessive inheritance pattern, as suggested by pedigrees, variants discovered in our study were exclusively bi-allelic and mostly in a homozygous state (in 15 families out of 17, or 88%). Out of the 17 variants identified, 5 (29%) were never reported before. Interestingly, two mutations (GUCY2D:c.564dup, p.Ala189ArgfsTer130 and TULP1:c.1199G > A, p.Arg400Gln) were also identified in four separate pedigrees (two pedigrees each). In addition to expanding the mutational spectrum of IRDs, our findings confirm that the traditional practice of endogamy in the Iranian population is a prime cause for the appearance of IRDs.

scholarly journals A Novel COMP Mutated Allele Identified in a Chinese Family with Pseudoachondroplasia

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Bing-Bing Guo ◽  
Jie-Yuan Jin ◽  
Zhuang-Zhuang Yuan ◽  
Lei Zeng ◽  
Rong Xiang
Keyword(s):  
Extracellular Matrix ◽  
Cartilage Oligomeric Matrix Protein ◽  
Matrix Protein ◽  
Autosomal Dominant ◽  
Novel Mutation ◽  
Chinese Family ◽  
The Novel ◽  
Structure Model ◽  
Whole Exome ◽  
Nucleotide Mutation

Pseudoachondroplasia (PSACH) is an autosomal dominant skeletal dysplasia with an estimated incidence of ~1/60000 that is characterized by disproportionate short stature, brachydactyly, joint laxity, and early-onset osteoarthritis. COMP encodes the cartilage oligomeric matrix protein, which is expressed predominantly in the extracellular matrix (ECM) surrounding the cells that make up cartilage, ligaments, and tendons. Mutations in COMP are known to give rise to PSACH. In this study, we identified a novel nucleotide mutation (NM_000095.2: c.1317C>G, p.D439E) in COMP responsible for PSACH in a Chinese family by employing whole-exome sequencing (WES) and built the structure model of the mutant protein to clarify its pathogenicity. The novel mutation cosegregated with the affected individuals. Our study expands the spectrum of COMP mutations and further provides additional genetic testing information for other PSACH patients.

scholarly journals Cochlear Implantation in a Patient with a Novel POU3F4 Mutation and Incomplete Partition Type-III Malformation

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Xiuhua Chao ◽  
Yun Xiao ◽  
Fengguo Zhang ◽  
Jianfen Luo ◽  
Ruijie Wang ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Cochlear Implantation ◽  
Novel Mutation ◽  
Clinical Manifestations ◽  
Bioinformatic Analysis ◽  
Chinese Family ◽  
Whole Exome ◽  
Novel Variant ◽  
Genetic Features ◽  
The Right

Aims. This study is aimed at (1) analyzing the clinical manifestations and genetic features of a novel POU3F4 mutation in a nonsyndromic X-linked recessive hearing loss family and (2) reporting the outcomes of cochlear implantation in a patient with this mutation. Methods. A patient who was diagnosed as the IP-III malformation underwent cochlear implantation in our hospital. The genetic analysis was conducted in his family, including the whole-exome sequencing combined with Sanger sequencing and bioinformatic analysis. Clinical features, preoperative auditory and speech performances, and postoperative outcomes of cochlear implant (CI) were assessed on the proband and his family. Results. A novel variant c.400_401insACTC (p.Q136LfsX58) in the POU3F4 gene was detected in the family, which was cosegregated with the hearing loss. This variant was absent in 200 normal-hearing persons. The phylogenetic analysis and structure modeling of Pou3f4 protein further confirmed that the novel mutation was pathogenic. The proband underwent cochlear implantation on the right ear at four years old and gained greatly auditory and speech improvement. However, the benefits of the CI declined about three and a half years postoperation. Though the right ear had been reimplanted, the outcomes were still worse than before. Conclusion. A novel frame shift variant c.400_401insACTC (p.Q136LfsX58) in the POU3F4 gene was identified in a Chinese family with X-linked inheritance hearing loss. A patient with this mutation and IP-III malformation could get good benefits from CI. However, the outcomes of the cochlear implantation might decline as the patient grows old.

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