共查询到20条相似文献,搜索用时 31 毫秒
1.
Rongrong Wang Shuanghao Yang Ming Xu Jia Huang Hongyan Liu Weiyue Gu Xue Zhang 《中国科学:生命科学英文版》2018,61(8):947-953
Hereditary spherocytosis(HS), the most common cause of congenital hemolytic anemia, is caused by deficiency of the erythrocyte membrane proteins. Five causative genes(ANK1, SPTB, SPTA1, SLC4 A1, and EPB42) have been identified. To date,molecular genetic studies have been performed in different populations, including the American, European, Brazilian, Japanese and Korean populations, whereas only a few studies have been described in the Chinese population. Here, by reanalysis of the exome data, we revealed causative mutations and established a definitive diagnosis of HS in all 38 Chinese families. We found 34 novel mutations and four reported mutations in three known HS-causing genes—17 in ANK1, 17 in SPTB and four in SLC4 A1,suggesting that ANK1 and SPTB are the major genes in Chinese patients with HS. All of the ANK1 or SPTB mutations, scattered throughout the entire genes, are non-recurrent; and most of them are null mutations, which might cause HS via a haploinsufficiency mechanism. De novo mutations in ANK1 or SPTB often occur with an unexpected high frequency(87.5% and64.2%, respectively). Our study updates our knowledge about the genetic profile of HS in Chinese and shows that family-based,especially parent-offspring trio, sequencing analysis can help to increase the diagnostic power and improve diagnostic efficiency. 相似文献
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Lili Hao Shanshan Li Duan Ma Shiyu Chen Bowen Zhang Deyong Xiao Jin Zhang Nan Jiang Shayi Jiang Jing Ma 《Journal of cellular and molecular medicine》2019,23(6):4454-4463
Hereditary spherocytosis (HS) is the most common inherited haemolytic anaemia disorder. ANK1 mutations account for most HS cases, but pathogenicity analysis and functional research have not been widely performed for these mutations. In this study, in order to confirm diagnosis, gene mutation was screened in two unrelated Chinese families with HS by a next‐generation sequencing (NGS) panel and then confirmed by Sanger sequencing. Two novel heterozygous mutations (c.C841T, p.R281X and c.T290G, p.L97R) of the ANK1 gene were identified in the two families respectively. Then, the pathogenicity of the two new mutations and two previously reported ANK1 mutations (c.C648G, p.Y216X and c.G424T, p.E142X) were studied by in vitro experiments. The four mutations increased the osmotic fragility of cells, reduced the stabilities of ANK1 proteins and prevented the protein from localizing to the plasma membrane and interacting with SPTB and SLC4A1. We classified these four mutations into disease‐causing mutations for HS. Thus, conducting the same mutation test and providing genetic counselling for the two families were meaningful and significant. Moreover, the identification of two novel mutations enriches the ANK1 mutation database, especially in China. 相似文献
4.
Next-generation sequencing technology allows simultaneous analysis of multiple susceptibility genes for clinical cancer genetics. In this study, multiplex genetic testing was conducted in a Chinese family with multiple cases of cancer to determine the variations in cancer predisposition genes. The family comprises a mother and her five daughters, of whom the mother and the eldest daughter have cancer and the secondary daughter died of cancer. We conducted multiplex genetic testing of 90 cancer susceptibility genes using the peripheral blood DNA of the mother and all five daughters. WRN frameshift mutation is considered a potential pathogenic variation according to the guidelines of the American College of Medical Genetics. A novel WRN frameshift mutation (p.N1370Tfs*23) was identified in the three cancer patients and in the youngest unaffected daughter. Other rare non-synonymous germline mutations were also detected in DICER and ELAC2. Functional mutations in WRN cause Werner syndrome, a human autosomal recessive disease characterized by premature aging and associated with genetic instability and increased cancer risk. Our results suggest that the WRN frameshift mutation is important in the surveillance of other members of this family, especially the youngest daughter, but the pathogenicity of the novel WRN frameshift mutation needs to be investigated further. Given its extensive use in clinical genetic screening, multiplex genetic testing is a promising tool in clinical cancer surveillance. 相似文献
5.
Genome-wide identification and expression profiling of ankyrin-repeat gene family in maize 总被引:1,自引:0,他引:1
Haiyang Jiang Qingqing Wu Jing Jin Lei Sheng Hanwei Yan Beijiu Cheng Suwen Zhu 《Development genes and evolution》2013,223(5):303-318
Members of the ankyrin repeats (ANK) gene family encode ANK domain that are common in diverse organisms and play important roles in cell growth and development, such as cell-cell signal transduction and cell cycle regulation. Recently, genome-wide identification and evolutionary analyses of the ANK gene family have been carried out in Arabidopsis and rice. However, little is known regarding the ANK genes in the entire maize genome. In this study, we described the identification and structural characterization of 71 ANK genes in maize (ZmANK). Then, comprehensive bioinformatics analyses of ZmANK genes family were performed including phylogenetic, domain and motif analysis, chromosomal localization, intron/exon structural patterns, gene duplications and expression profiling. Domain composition analyses showed that ZmANK genes formed ten subfamilies. Five tandem duplications and 14 segmental duplications were identified in ZmANK genes. Furthermore, we took comparative analysis of the total ANK gene family in Arabidopsis, rice and maize, ZmANKs were more closely paired with OsANKs than with AtANKs. At last, expression profile analyses were performed. Forty-one members of ZmANK genes held EST sequences records. Semi-quantitative expression and microarray data analysis of these 41 ZmANK genes demonstrated that ZmANK genes exhibit a various expression pattern, suggesting that functional diversification of ZmANK genes family. The results will present significant insights to explore ANK genes expression and function in future studies in maize. 相似文献
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Xiangjun Huang Xiong Deng Hongbo Xu Song Wu Lamei Yuan Zhijian Yang Yan Yang Hao Deng 《PloS one》2015,10(6)
Spondyloepiphyseal dysplasia congenita (SEDC) is an autosomal dominant chondrodysplasia characterized by disproportionate short-trunk dwarfism, skeletal and vertebral deformities. Exome sequencing and Sanger sequencing were performed in a Chinese Han family with typical SEDC, and a novel mutation, c.620G>A (p.Gly207Glu), in the collagen type II alpha-1 gene (COL2A1) was identified. The mutation may impair protein stability, and lead to dysfunction of type II collagen. Family-based study suggested that the mutation is a de novo mutation. Our study extends the mutation spectrum of SEDC and confirms genotype-phenotype relationship between mutations at glycine in the triple helix of the alpha-1(II) chains of the COL2A1 and clinical findings of SEDC, which may be helpful in the genetic counseling of patients with SEDC. 相似文献
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Nara L. M. Sobreira Elizabeth T. Cirulli Dimitrios Avramopoulos Elizabeth Wohler Gretchen L. Oswald Eric L. Stevens Dongliang Ge Kevin V. Shianna Jason P. Smith Jessica M. Maia Curtis E. Gumbs Jonathan Pevsner George Thomas David Valle Julie E. Hoover-Fong David B. Goldstein 《PLoS genetics》2010,6(6)
Although more than 2,400 genes have been shown to contain variants that cause Mendelian disease, there are still several thousand such diseases yet to be molecularly defined. The ability of new whole-genome sequencing technologies to rapidly indentify most of the genetic variants in any given genome opens an exciting opportunity to identify these disease genes. Here we sequenced the whole genome of a single patient with the dominant Mendelian disease, metachondromatosis (OMIM 156250), and used partial linkage data from her small family to focus our search for the responsible variant. In the proband, we identified an 11 bp deletion in exon four of PTPN11, which alters frame, results in premature translation termination, and co-segregates with the phenotype. In a second metachondromatosis family, we confirmed our result by identifying a nonsense mutation in exon 4 of PTPN11 that also co-segregates with the phenotype. Sequencing PTPN11 exon 4 in 469 controls showed no such protein truncating variants, supporting the pathogenicity of these two mutations. This combination of a new technology and a classical genetic approach provides a powerful strategy to discover the genes responsible for unexplained Mendelian disorders. 相似文献
9.
Xiran Wang Yu Pei Jingtao Dou Juming Lu Jian Li Zhaohui Lv 《Genetics and molecular biology》2015,38(1):1-7
Osteogenesis imperfecta (OI) is a family of genetic disorders associated with bone
loss and fragility. Mutations associated with OI have been found in genes encoding
the type I collagen chains. People with OI type I often produce insufficient α1-chain
type I collagen because of frameshift, nonsense, or splice site mutations in
COL1A1 or COL1A2. This report is of a Chinese
daughter and mother who had both experienced two bone fractures. Because skeletal
fragility is predominantly inherited, we focused on identifying mutations in
COL1A1 and COL1A2 genes. A novel mutation in
COL1A1, c.700delG, was detected by genomic DNA sequencing in the
mother and daughter, but not in their relatives. The identification of this mutation
led to the conclusion that they were affected by mild OI type I. Open reading frame
analysis indicated that this frameshift mutation would truncate α1-chain type I
collagen at residue p263 (p.E234KfsX264), while the wild-type protein would contain
1,464 residues. The clinical data were consistent with the patients’ diagnosis of
mild OI type I caused by haploinsufficiency of α1-chain type I collagen. Combined
with previous reports, identification of the novel mutation
COL1A1-c.700delG in these patients suggests that
additional genetic and environmental factors may influence the severity of OI. 相似文献
10.
Hee-Jin Kim Hong-Hee Won Kyoung-Jin Park Sung Hwa Hong Chang-Seok Ki Sang Sun Cho Hanka Venselaar Gert Vriend Jong-Won Kim 《PloS one》2013,8(11)
Autosomal dominant non-syndromic hearing loss (AD-NSHL) is one of the most common genetic diseases in human and is well-known for the considerable genetic heterogeneity. In this study, we utilized whole exome sequencing (WES) and linkage analysis for direct genetic diagnosis in AD-NSHL. The Korean family had typical AD-NSHL running over 6 generations. Linkage analysis was performed by using genome-wide single nucleotide polymorphism (SNP) chip and pinpointed a genomic region on 5q31 with a significant linkage signal. Sequential filtering of variants obtained from WES, application of the linkage region, bioinformatic analyses, and Sanger sequencing validation identified a novel missense mutation Arg326Lys (c.977G>A) in the POU homeodomain of the POU4F3 gene as the candidate disease-causing mutation in the family. POU4F3 is a known disease gene causing AD-HSLH (DFNA15) described in 5 unrelated families until now each with a unique mutation. Arg326Lys was the first missense mutation affecting the 3rd alpha helix of the POU homeodomain harboring a bipartite nuclear localization signal sequence. The phenotype findings in our family further supported previously noted intrafamilial and interfamilial variability of DFNA15. This study demonstrated that WES in combination with linkage analysis utilizing bi-allelic SNP markers successfully identified the disease locus and causative mutation in AD-NSHL. 相似文献
11.
《Saudi Journal of Biological Sciences》2023,30(2):103520
Hearing loss (HL) is the most prevalent sensory disorder whose etiology comes from environmental and/or genetic factors. Approximately 60 % of HL cases are due to mutations in genes responsible for maintaining a normal hearing function. Despite the monogenic inheritance of hereditary hearing loss (HHL), its diagnosis is challenging as both clinical and genetic heterogeneity characterizes it. Through the development of next-generation sequencing (NGS) techniques, the number of identified mutations responsible for HHL has increased exponentially during the last decade. Mutations in the TMC1 have been reported in several patients with nonsyndromic hereditary hearing loss (NSHHL), more precisely in cases with an autosomal recessive inheritance pattern. In this study, we conducted whole-exome sequencing (WES) analysis of a United Arabs Emirates (UAE) family with autosomal recessive nonsyndromic hearing loss (ARNSHL). This analysis revealed segregation of the TMC1 missense mutation c.596A > T (p.Asn199Ile) with the disease. Bioinformatics analysis supported the pathogenic effect of this mutation and predicted its impact at the proteomics level. Molecular docking analysis of TMC2WT, TMC2R123K, TMC2Q205R, and TMC2R123K + Q205R. Finally, protein docking results suggest a role for TMC2 variants in the phenotypic variability observed within the investigated family. 相似文献
12.
Fatih Kardas Asli Subasioglu Uzak Mohammad Arif Hossain Norio Sakai Mehmet Canpolat Ali Yıkılmaz 《Gene》2013
A clear cut genotype–phenotype correlation for Krabbe disease is not available. Therefore, it is important to identify new mutations and their associated phenotypes to predict the prognosis of the disease. The aim of this study is to identify the causative mutation(s) in a family with Krabbe disease. After a clinical evaluation and suspicion of Krabbe disease galactocerebrosidase activity was analyzed and GALC gene mutation analysis was performed. The galactocerebrosidase enzyme activity was 0.01 nmol/mg/h protein (normal range 0.8–4). For further investigation mutation screening was performed by Sanger sequencing across the 17 exons of GALC gene. A novel homozygous mutation c.727delT (p.S243QfsX7) was found. In this study we present the clinical findings along with a novel GALC mutation in a consanguineous Turkish family. Although the relationship between the various genotypes and phenotypes in Krabbe disease has not been fully elucidated an accurate genetic family study is helpful for genetic counseling follow-up and therapy of Krabbe disease. Also, it is important to identify new mutations in order to clarify their clinical importance, to assess the prognosis of the disease, and to suggest either prenatal diagnosis or preimplantation genetic diagnosis to the effected families. 相似文献
13.
Seung-Hyun Bae Jeong-In Baek Jong Dae Lee Mee Hyun Song Tae-Jun Kwon Se-Kyung Oh Ji Yun Jeong Jae Young Choi Kyu-Yup Lee Un-Kyung Kim 《Gene》2013
Auditory neuropathy spectrum disorder (ANSD) is caused by dys-synchronous auditory neural response as a result of impairment of the functions of the auditory nerve or inner hair cells, or synapses between inner hair cells and the auditory nerve. To identify a causative gene causing ANSD in the Korean population, we conducted gene screening of the OTOF, DIAPH3, and PJVK genes in 19 unrelated Korean patients with ANSD. A novel nonsense mutation (p.Y1064X) and a known pathogenic mutation (p.R1939Q) of the OTOF gene were identified in a patient as compound heterozygote. Pedigree analysis for these mutations showed co-segregation of mutation genotype and the disease in the family, and it supported that the p.Y1064X might be a novel genetic cause of autosomal recessive ANSD. A novel missense variant p.K1017R (c.3050A>G) in the DIAPH3 gene was also identified in the heterozygous state. In contrast, no mutation was detected in the PJVK gene. These results indicate that no major causative gene has been reported to date in the Korean population and that pathogenic mutations in undiscovered candidate genes may have an effect on ANSD. 相似文献
14.
Yilu Wang Zhimin Wang Qi Yang Yubao Zou Hongju Zhang Chaowu Yan Xinxing Feng Yi Chen Yin Zhang Jizheng Wang Xianliang Zhou Ferhaan Ahmad Rutai Hui Lei Song 《PloS one》2013,8(6)
Background
Hypertrophic cardiomyopathy (HCM) due to mutations in genes encoding sarcomere proteins is most commonly inherited as an autosomal dominant trait. Since nearly 50% of HCM cases occur in the absence of a family history, a recessive inheritance pattern may be involved.Methods
A pedigree was identified with suspected autosomal recessive transmission of HCM. Twenty-six HCM-related genes were comprehensively screened for mutations in the proband with targeted second generation sequencing, and the identified mutation was confirmed with bi-directional Sanger sequencing in all family members and 376 healthy controls.Results
A novel missense mutation (c.1469G>T, p.Gly490Val) in exon 17 of MYBPC3 was identified. Two siblings with HCM were homozygous for this mutation, whereas other family members were either heterozygous or wild type. Clinical evaluation showed that both homozygotes manifested a typical HCM presentation, but none of others, including 5 adult heterozygous mutation carriers up to 71 years of age, had any clinical evidence of HCM.Conclusions
Our data identified a MYBPC3 mutation in HCM, which appeared autosomal recessively inherited in this family. The absence of a family history of clinical HCM may be due to not only a de novo mutation, but also recessive mutations that failed to produce a clinical phenotype in heterozygous family members. Therefore, consideration of recessive mutations leading to HCM is essential for risk stratification and genetic counseling. 相似文献15.
Chun-Chi Lai Yung-Hsin Yeh Wen-Ping Hsieh Chi-Tai Kuo Wen-Ching Wang Chia-Han Chu Chiu-Lien Hung Chia-Yang Cheng Hsin-Yi Tsai Jia-Lin Lee Chuan-Yi Tang Lung-An Hsu 《PloS one》2013,8(12)
Background
Inherited cardiac conduction diseases (CCD) are rare but are caused by mutations in a myriad of genes. Recently, whole-exome sequencing has successfully led to the identification of causal mutations for rare monogenic Mendelian diseases.Objective
To investigate the genetic background of a family affected by inherited CCD.Methods and Results
We used whole-exome sequencing to study a Chinese family with multiple family members affected by CCD. Using the pedigree information, we proposed a heterozygous missense mutation (c.G695T, Gly232Val) in the lamin A/C (LMNA) gene as a candidate mutation for susceptibility to CCD in this family. The mutation is novel and is expected to affect the conformation of the coiled-coil rod domain of LMNA according to a structural model prediction. Its pathogenicity in lamina instability was further verified by expressing the mutation in a cellular model.Conclusions
Our results suggest that whole-exome sequencing is a feasible approach to identifying the candidate genes underlying inherited conduction diseases. 相似文献16.
Tiecheng Liu Xin Jin Xuemin Zhang Huijun Yuan Jing Cheng Janet Lee Baoquan Zhang Maonian Zhang Jing Wu Lijuan Wang Geng Tian Weifeng Wang 《PloS one》2012,7(9)
The SNRNP200 gene encodes hBrr2, a helicase essential for pre-mRNA splicing. Six mutations in SNRNP200 have recently been discovered to be associated with autosomal dominant retinitis pigmentosa (adRP). In this work, we analyzed a Chinese family with adRP and identified a novel missense mutation in SNRNP200. To identify the genetic defect in this family, exome of the proband was captured and sequencing analysis was performed to exclude known genetic defects and find possible pathogenic mutations. Subsequently, candidate mutations were validated in affected family members using Sanger sequencing. A novel missense mutation, c.2653C>G transition (p.Q885E), in exon 20 of SNRNP200 was identified. The mutation co-segregated with the disease phenotype over four generations and was absent in 100 normal unaffected individuals. This mutation occurs at highly conserved position in hBrr2 and is predicted to have a functional impact, suggesting that hBrr2-dependent small nuclear riboproteins (snRNPs) unwinding and spliceosome activation is important in the pathogenesis of some variants of RP. 相似文献
17.
Targeted Next-Generation Sequencing in Uyghur Families with Non-Syndromic Sensorineural Hearing Loss
Ying Chen Zhentao Wang Zhaoyan Wang Dongye Chen Yongchuan Chai Xiuhong Pang Lianhua Sun Xiaowen Wang Tao Yang Hao Wu 《PloS one》2015,10(5)
The mutation spectrum of deafness genes may vary in different ethnical groups. In this study, we investigated the genetic etiology of nonsyndromic deafness in four consanguineous and two multiplex Uyghur families in which mutations in common deafness genes GJB2, SLC26A4 and MT-RNR1 were excluded. Targeted next-generation sequencing of 97 deafness genes was performed in the probands of each family. Novel pathogenic mutations were identified in four probands including the p.L416R/p.A438T compound heterozygous mutations in TMC1, the homozygous p.V1880E mutation in MYO7A, c.1238delT frameshifting deletion in PCDH15 and c.9690+1G>A splice site mutation in MYO15A. Co-segregation of the mutations and the deafness were confirmed within each family by Sanger sequencing. No pathogenic mutations were identified in one multiplex family and one consanguineous family. Our study provided a useful piece of information for the genetic etiology of deafness in Uyghurs. 相似文献
18.
Charlotte Mouden Marie de Tayrac Christèle Dubourg Sophie Rose Wilfrid Carré Houda Hamdi-Rozé Marie-Claude Babron Linda Akloul Bénédicte Héron-Longe Sylvie Odent Valérie Dupé Régis Giet Véronique David 《PloS one》2015,10(2)
Holoprosencephaly (HPE) is a frequent congenital malformation of the brain characterized by impaired forebrain cleavage and midline facial anomalies. Heterozygous mutations in 14 genes have been identified in HPE patients that account for only 30% of HPE cases, suggesting the existence of other HPE genes. Data from homozygosity mapping and whole-exome sequencing in a consanguineous Turkish family were combined to identify a homozygous missense mutation (c.2150G>A; p.Gly717Glu) in STIL, common to the two affected children. STIL has a role in centriole formation and has previously been described in rare cases of microcephaly. Rescue experiments in U2OS cells showed that the STIL p.Gly717Glu mutation was not able to fully restore the centriole duplication failure following depletion of endogenous STIL protein indicating the deleterious role of the mutation. In situ hybridization experiments using chick embryos demonstrated that expression of Stil was in accordance with a function during early patterning of the forebrain. It is only the second time that a STIL homozygous mutation causing a recessive form of HPE was reported. This result also supports the genetic heterogeneity of HPE and increases the panel of genes to be tested for HPE diagnosis. 相似文献
19.
Hong Xia Xiangjun Huang Yi Guo Pengzhi Hu Guangxiang He Xiong Deng Hongbo Xu Zhijian Yang Hao Deng 《PloS one》2015,10(8)
Autosomal recessive nonsyndromic hearing loss (ARNSHL) is a genetically heterogeneous sensorineural disorder, generally manifested with prelingual hearing loss and absence of other clinical manifestations. The aim of this study is to identify the pathogenic gene in a four-generation consanguineous Chinese family with ARNSHL. A novel homozygous variant, c.9316dupC (p.H3106Pfs*2), in the myoxin XVa gene (MYO15A) was identified by exome sequencing and Sanger sequencing. The homozygous MYO15A c.9316dupC variant co-segregated with the phenotypes in the ARNSHL family and was absent in two hundred normal controls. The variant was predicted to interfere with the formation of the Myosin XVa-whirlin-Eps8 complex at the tip of stereocilia, which is indispensable for stereocilia elongation. Our data suggest that the homozygous MYO15A c.9316dupC variant might be the pathogenic mutation, and exome sequencing is a powerful molecular diagnostic strategy for ARNSHL, an extremely heterogeneous disorder. Our findings extend the mutation spectrum of the MYO15A gene and have important implications for genetic counseling for the family. 相似文献
20.
Fang Lu Lulin Huang Chuntao Lei Guiquan Sha Hong Zheng Xiaoqi Liu Jiyun Yang Yi Shi Ying Lin Bo Gong Xianjun Zhu Shi Ma Lifeng Qiao He Lin Jing Cheng Zhenglin Yang 《PloS one》2013,8(11)