scholarly journals FLNC and MYLK2 gene mutations in a Chinese family with different phenotypes of cardiomyopathy

2020 ◽  
Author(s):  
Xianyu Qin ◽  
Ping Li ◽  
Hui-Qi Qu ◽  
Yichuan Liu ◽  
Yu Xia ◽  
...  
Keyword(s):  
Family Member ◽  
Novel Mutation ◽  
Gene Mutations ◽  
Chinese Family ◽  
Wild Type ◽  
Human Cardiomyocytes ◽  
Sarcomeric Protein ◽  
Truncating Mutation ◽  
Whole Exome ◽  
Type Gene

Abstract Background Mutations in the sarcomeric protein filamin C (FLNC) gene have been linked to hypertrophic cardiomyopathy (HCM), in which they increase the risk of ventricular arrhythmia and sudden death. In this study, we identified a novel missense mutation of FLNC in a Chinese family with HCM and interestingly a second novel truncating mutation of MYLK2 in one family member with different phenotype. Methods We performed whole-exome sequencing in a Chinese family with HCM of unknown cause. To validate the function of a novel mutation of FLNC, we introduced the mutant and wild-type gene into AC16 cells (human cardiomyocytes), and used western blotting to analyze the expression of FLNC in subcellular fractions, and confocal microscope to observe the subcellular distribution of the protein. Results We identified a novel missense single nucleotide variant (FLNC c.G5935A [p.A1979T]) in the family, which segregates with the disease. FLNC expression levels were equivalent in both wild type and p.A1979T cardiomyocytes. However, expression of the mutant protein resulted in cytoplasmic protein aggregations, in contrast to wild type FLNC, which was distributed in the cytoplasm and did not form aggregates. Unexpectely, a second truncating mutation, NM_033118:exon8:c.G1138T:p.E380X of the MYLK2 gene, was identified in the mother of the proband with dilated cardiomyopathy, but absent in other subjects. Conclusion We identified the FLNC A1979T mutation as a novel pathogenic variant associated with HCM in a Chinese family, as well as a second causal mutation in a family member with a distinct phenotype. The possibility of more than one causal mutations in cardiomyopathy warrants clinical attention, especially for patients with atypical clinical features.

scholarly journals FLNC and MYLK2 gene mutations in a Chinese family with different phenotypes of cardiomyopathy

2020 ◽  
Author(s):  
Xianyu Qin ◽  
Ping Li ◽  
Huiqi Qu ◽  
Yichuan Liu ◽  
Yu Xia ◽  
...  
Keyword(s):  
Family Member ◽  
Novel Mutation ◽  
Gene Mutations ◽  
Chinese Family ◽  
Wild Type ◽  
Human Cardiomyocytes ◽  
Sarcomeric Protein ◽  
Truncating Mutation ◽  
Whole Exome ◽  
Type Gene

Background: Mutations in the sarcomeric protein filamin C (FLNC) gene have been linked to hypertrophic cardiomyopathy (HCM), in which they increase the risk of ventricular arrhythmia and sudden death. In this study, we identified a novel missense mutation of FLNC in a Chinese family with HCM and interestingly a second novel truncating mutation of MYLK2 in one family member with different phenotype. Methods: We performed whole-exome sequencing in a Chinese family with HCM of unknown cause. To validate the function of a novel mutation of FLNC, we introduced the mutant and wild-type gene into AC16 cells (human cardiomyocytes), and used western blotting to analyze the expression of FLNC in subcellular fractions, and confocal microscope to observe the subcellular distribution of the protein. Results: We identified a novel missense single nucleotide variant (FLNC c.G5935A [p.A1979T]) in the family, which segregates with the disease. FLNC expression levels were equivalent in both wild type and p.A1979T cardiomyocytes. However, expression of the mutant protein resulted in cytoplasmic protein aggregations, in contrast to wild type FLNC, which was distributed in the cytoplasm and did not form aggregates. Unexpectely, a second truncating mutation, NM_033118:exon8:c.G1138T:p.E380X of the MYLK2 gene, was identified in the mother of the proband with dilated cardiomyopathy, but absent in other subjects. Conclusion: We identified the FLNC A1979T mutation as a novel pathogenic variant associated with HCM in a Chinese family, as well as a second causal mutation in a family member with a distinct phenotype. The possibility of more than one causal mutations in cardiomyopathy warrants clinical attention, especially for patients with atypical clinical features.

scholarly journals Novel compound heterozygous EYS variants may be associated with arRP in a large Chinese pedigree

2020 ◽  
Vol 40 (6) ◽  
Author(s):  
Chunli Wei ◽  
Ting Xiao ◽  
Jingliang Cheng ◽  
Jiewen Fu ◽  
Qi Zhou ◽  
...  
Keyword(s):  
Novel Mutation ◽  
Gene Mutations ◽  
Chinese Family ◽  
Compound Heterozygous ◽  
Missense Mutations ◽  
The Novel ◽  
Pathogenic Variants ◽  
Pathogenic Genes ◽  
Compound Heterozygous Variants ◽  
Normal Controls

Abstract As a genetically heterogeneous ocular dystrophy, gene mutations with autosomal recessive retinitis pigmentosa (arRP) in patients have not been well described. We aimed to detect the disease-causing genes and variants in a Chinese arRP family. In the present study, a large Chinese pedigree consisting of 31 members including a proband and another two patients was recruited; clinical examinations were conducted; next-generation sequencing using a gene panel was used for identifying pathogenic genes, and Sanger sequencing was performed for verification of mutations. Novel compound heterozygous variants c.G2504A (p.C835Y) and c.G6557A (p.G2186E) for the EYS gene were identified, which co-segregated with the clinical RP phenotypes. Sequencing of 100 ethnically matched normal controls didn’t found these mutations in EYS. Therefore, our study identified pathogenic variants in EYS that may cause arRP in this Chinese family. This is the first study to reveal the novel mutation in the EYS gene (c.G2504A, p.C835Y), extending its mutation spectrum. Thus, the EYS c.G2504A (p.C835Y) and c.G6557A (p.G2186E) variants may be the disease-causing missense mutations for RP in this large arRP family. These findings should be helpful for molecular diagnosis, genetic counseling and clinical management of arRP disease.

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.

scholarly journals Identification of a novel mutation in a Chinese family with Nance-Horan syndrome by whole exome sequencing

2014 ◽  
Vol 15 (8) ◽  
pp. 727-734 ◽  
Author(s):  
Nan Hong ◽  
Yan-hua Chen ◽  
Chen Xie ◽  
Bai-sheng Xu ◽  
Hui Huang ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Novel Mutation ◽  
Chinese Family ◽  
Whole Exome

Gene Mutations Identified in Chemorefractory Acute Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3838-3838
Author(s):  
Anthony Palmer ◽  
Brian Parkin ◽  
Hidde Posthuma ◽  
Shin Mineishi ◽  
John M. Magenau ◽  
...  
Keyword(s):  
Gene Mutations ◽  
Refractory Disease ◽  
Wild Type ◽  
Discovery Cohort ◽  
Protein Coding ◽  
Tp53 Mutations ◽  
Whole Exome ◽  
Equity Ownership ◽  
Secondary Refractory ◽  
Refractory Aml

Abstract Introduction: Acute myeloid leukemia (AML) is a genetically heterogeneous disease. Recently, multiple recurrently mutated genes have been identified in AML and implicated in various mechanisms of leukemogenesis. However, knowledge regarding the association of gene mutations with primary or secondary resistance to chemotherapy is incomplete. Methods: We analyzed a discovery cohort of 45 patients with chemorefractory AML that were enrolled in a phase 2 clinical trial of a novel conditioning regimen prior to allogeneic stem cell transplant for patients with non-remission AML. DNA was extracted from FACS-purified leukemic cells procured from patients after failure to achieve complete remission (CR) after ≥2 cycles of induction chemotherapy after initial diagnosis ("primary refractory", N=22) or after rapid relapse (<6 months) or failure to achieve CR after ≥1 cycle of induction chemotherapy after relapse ("secondary refractory", N=23). Since TP53 mutations have been previously associated with refractory disease, we selected 29 TP53 wild-type cases from the discovery cohort and performed whole exome sequencing (WES) with a mean read depth of 72X (range 30-140). All somatically acquired gene variants identified by WES in protein-coding genes were verified by Sanger sequencing. In addition, we performed Sanger re-sequencing of 11 recurrently mutated genes in AML (TP53, RUNX1, DNMT3A, TET2, FLT3, NPM1, IDH1, IDH2, ASXL1, NRAS and KRAS) in all 45 cases. Given lack of published WES data in refractory AML, we then compared these mutation frequencies to a cohort of 151 AML patients enrolled consecutively at one center (the "university cohort") with known responses to chemotherapy or The Cancer Genome Atlas (TCGA) data which comprises de novo AML only. Results: WES of 29 TP53 wild-type refractory AML cases revealed a total of 351 confirmed somatic mutations with a median of 13 protein-coding mutations per case (range 5-22). Genes mutated in 7% (2 of 29 cases), and excluding the 11 known recurrently mutated genes listed above, that were not previously described in AML (COSMIC review) included ADAM23, CPNE7, and SIX5. We also identified mutations in NOMO3 and OAS2 in 7% (2 of 29 cases), which have been previously described in AML but at lower frequencies (1.7% [6 of 347; COSMIC] and 0.2% [1 of 347] respectively) based on review of the literature. The genes SRSF2, NOMO3 and OAS2, which were all identified in 7% (2 of 29 cases) in our discovery cohort, had no reported mutations found in the TCGA (p=0.02). Additional genes, which were found in our discovery cohort in 7% (2 of 29 cases) respectively, and were also found in the TCGA, include BCOR, FOXP1, FRYL, PHF6, STAG2, PTPN11 and SETD2. Mutational profiling of the 11 recurrently mutated genes in AML revealed a striking paucity of NPM1 mutations in primary refractory AML (range 0% [discovery cohort] - 3% [university cohort]) compared with chemosensitive AML (31% [university cohort]; p<0.001). TP53 mutations, however, were enriched in primary refractory AML (range 23% [discovery cohort] - 38% [university cohort]) compared with chemosensitive AML (4% [university cohort]; p<0.001). Of note, while FLT3 -ITD mutations were infrequently observed in primary refractory AML (range 0% [discovery cohort] - 14% [university cohort]) compared to chemosensitive AML (27% [university cohort]; p<0.01), they were highly enriched in secondary refractory AML (61% [discovery cohort] - 30% [university cohort]; p=0.03). Conclusions: 1) Whole exome sequencing of 29 TP53 wild-type refractory AML revealed recurrent mutations in ADAM23, CPNE7, NOMO3, OAS2 and SIX5. The function and prevalence of these gene mutations are not well-characterized in AML, including refractory AML and should be determined in a larger cohort of patients; 2) TP53 mutations were significantly enriched in primary refractory disease; 3) Conversely, FLT3 -ITD mutations were significantly enriched in secondary but not primary refractory disease, suggesting the frequent emergence of a chemorefractory FLT3-ITD mutated clone following treatment with conventional chemotherapy; and, 4) NPM1 mutations were significantly under-represented in primary refractory AML. While larger sequencing studies of refractory AML cases are needed, these data do not support gene mutations other than in TP53 as frequent causes of primary refractoriness to chemotherapy in AML. Disclosures Malek: Gilead Sciences: Equity Ownership; Abbvie: Equity Ownership; Janssen Pharmaceuticals: Research Funding.

scholarly journals Heterozygous missense RAD21 variant in a peripheral sclerocornea pedigree

2019 ◽  
Author(s):  
Bi Ning Zhang ◽  
Tommy Chung Yan Chan ◽  
Pancy Oi Sin Tam ◽  
Yu Liu ◽  
Chi Pui Pang ◽  
...  
Keyword(s):  
Cell Lines ◽  
Genetic Variant ◽  
Mrna Level ◽  
Missense Variant ◽  
Genetic Alterations ◽  
Chinese Family ◽  
Wild Type ◽  
Whole Exome ◽  
Rare Congenital Disorder ◽  
Corneal Diameter

AbstractBackgroundSclerocomea is a rare congenital disorder characterized with cornea opacification. We identified a heterozygous missense RAD21 variant in a non-cons anguineous Chinese family with multiple peripheral sclerocomea patients spanning across three generations inherited in an autosomal dominant manner.MethodsComprehensive ophthalmic examinations were conducted on all 14 members. Whole exome sequencing was used to identify the genetic alterations in the affected pedigree members. Lymphoblastoid cell lines (LCLs) were established using blood samples from all members. Cleavage of RAD21 protein was quantified in these cell lines.ResultsAll affected individuals showed features of scleralization over the peripheral cornea of both eyes. Mean horizontal and vertical corneal diameter were significantly decreased in the affected members. Significant differences were also observed on mean apex pachymetry between affected and unaffected subjects. A RAD21C1348T variant was co-segregated with affected members. Both the wild-type allele and the missense variant were expressed at the mRNA level. This variant caused RAD21 R450C substitution at the separase cleavage site, which led to reduced RAD21 cleavage.ConclusionWe believe this is the first report of genetic variant in sclerocornea without other syndromes. Further work is needed to confirm the RAD21R450C variant with sclerocomea.

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