scholarly journals Clinical and Genetic Analyses of 38 Chinese Patients with Peutz-Jeghers Syndrome

2020 ◽  
Vol 2020 ◽  
pp. 1-12 ◽  
Author(s):  
Bo-Da Wu ◽  
Yong-Jun Wang ◽  
Liang-Liang Fan ◽  
Hui Huang ◽  
Peng Zhou ◽  
...  
Keyword(s):  
Direct Sequencing ◽  
Gene Mutations ◽  
Chinese Patients ◽  
Missense Mutations ◽  
Inherited Disease ◽  
Hamartomatous Polyps ◽  
Kaplan Meier ◽  
Genetic Features ◽  
The Difference ◽  
Peutz Jeghers Syndrome

Background. Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant inherited disease caused by a germline mutation in the STK11 gene. It is characterized by mucocutaneous pigmentation, gastrointestinal hamartomatous polyps, and cancer predisposition. Aims. We aimed to summarize the main clinical and genetic features of Chinese PJS patients and assessed the genotype-phenotype correlations. Methods. Thirty-eight patients clinically diagnosed with Peutz-Jeghers syndrome were included in this study from 2016 to 2019. Combined direct sequencing and multiplex ligation-dependent probe amplification tests were used to detect germline heterogeneous STK11 mutations. RNA sequencing was performed in polyps of PJS patients and control groups to evaluate the difference in expression of STK11. The genotype-phenotype correlations were calculated by Kaplan-Meier analyses. Results. All 26 probands and 12 affected relatives had germline heterogeneous STK11 mutations among which 8 variants were novel. Individuals with missense mutations had their first surgery and other symptoms significantly later than individuals with null mutations. Conclusion. This study expanded the spectrum of STK11 gene mutations and further elucidated individuals with null mutations of STK11 typically had an earlier onset of PJS symptoms and needed earlier management.

scholarly journals Analysis of genetic and clinical characteristics of a Chinese Kallmann syndrome cohort with ANOS1 mutations

2017 ◽  
Vol 177 (4) ◽  
pp. 389-398 ◽  
Author(s):  
Min Nie ◽  
Hongli Xu ◽  
Rongrong Chen ◽  
Jiangfeng Mao ◽  
Xi Wang ◽  
...  
Keyword(s):  
Clinical Characteristics ◽  
Clinical Presentation ◽  
Direct Sequencing ◽  
Gene Mutations ◽  
Kallmann Syndrome ◽  
Chinese Patients ◽  
Missense Mutations ◽  
The Novel ◽  
Novel Mutations ◽  
Functional Relevance

Objective To analyze ANOS1 gene mutations in a large Chinese Kallmann syndrome (KS) cohort and to characterize the clinical presentation of the disease in patients with ANOS1 mutations. Patients and methods Chinese patients with KS, including 187 sporadic and 23 pedigree cases were recruited. Patients’ ANOS1 gene sequences were analyzed by direct sequencing of PCR-amplified products. In silico analysis was used to assess functional relevance of newly identified missense mutations. Patients’ clinical characteristics were analyzed retrospectively. Result(s) Fifteen nonsynonymous rare ANOS1 variants were found in 13 out of 187 sporadic and 8 out of 23 familial IHH probands. Seven novel (C86F, C90Y, C151W, Y379X, c.1062 + 1G > A, Y579L fs 591X, R597X) and eight recurrent ANOS1 mutations (S38X, R257X, R262X, R423X, R424X, V560I, c.1843-1G > A, p.R631X) were identified. All the novel mutations were predicted to be pathogenic. The prevalence of cryptorchidism was high (38.1%) and occurred in patients with different kind of ANOS1 mutations, while the patients with the same mutation did not present with cryptorchidism uniformly. Conclusion(s) The prevalence of ANOS1 gene mutations is low in sporadic KS patients, but is much higher in familial KS patients. In the present study, we identify seven novel ANOS1 mutations, including two mutations in the CR domain, which are probably pathogenic. These mutations expand the ANOS1 mutation spectrum and provide a foundation for prenatal diagnosis and genetic counseling.

Abstract TP269: Distinct Molecular Mechanisms of Htra1 Mutants in Manifesting Heterozygotes With Carasil

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Hiroaki Nozaki ◽  
Taisuke Kato ◽  
Megumi Nihonmatsu ◽  
Yohei Saito ◽  
Ikuko Mizuta ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Molecular Mechanisms ◽  
Small Vessel Disease ◽  
Gel Filtration ◽  
Gene Mutations ◽  
Missense Mutations ◽  
Inherited Disease ◽  
Wild Type ◽  
Vessel Disease ◽  
Activation Cascade

Introduction: Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), an autosomal recessive inherited cerebral small vessel disease (CSVD), involves severe leukoaraiosis, multiple lacunar infarcts, early-onset alopecia, and spondylosis deformans. High-temperature requirement serine peptidase A1 (HTRA1) gene mutations cause CARASIL by decreasing HTRA1 protease activity. Although CARASIL is a recessive inherited disease, heterozygous mutations in the HTRA1 gene were recently identified in 11 families with CSVD. Because CSVD is frequently observed in elderly individuals, it is unclear which mutants truly contribute to CSVD pathogenesis. Here, we found heterozygous mutations in the HTRA1 gene in individuals with CSVD and investigated the differences in biochemical characteristics between these mutant HTRA1s and mutant HTRA1s observed in homozygotes. Methods: We recruited 113 unrelated index patients with clinically diagnosed CSVD. The coding sequences of the HTRA1 gene were analyzed. We evaluated HTRA1 protease activities using casein assays and oligomeric HTRA1 formation using gel filtration chromatography. Results: We found 4 heterozygous missense mutations in the HTRA1 gene (p.G283E, p.P285L, p.R302Q, and p.T319I) in 6 patients from 113 unrelated index patients and in 2 siblings in 2 unrelated families with p.R302Q. These mutant HTRA1s showed markedly decreased protease activities and inhibited wild-type HTRA1 activity, whereas 2 of 3 mutant HTRA1s reported in CARASIL (A252T and V297M) did not inhibit wild- type HTRA1 activity. Wild-type HTRA1 forms trimers; however, G283E and T319I HTRA1, observed in manifesting heterozygotes, did not form trimers. P285L and R302Q HTRA1s formed trimers, but their mutations were located in domains that are important for trimer-associated HTRA1 activation; in contrast, A252T and V297M HTRA1s, which have been observed in CARASIL, also formed trimers but had mutations outside the domains important for trimer- associated HTRA1 activation. Conclusions: The mutant HTRA1s observed in manifesting heterozygotes might result in an impaired HTRA1 activation cascade of HTRA1 or be unable to form stable trimers.

scholarly journals Ocular phenotype and genetical analysis in patients with retinopathy of prematurity

2022 ◽  
Vol 22 (1) ◽  
Author(s):  
Tianchang Tao ◽  
Xianfen Meng ◽  
Ningda Xu ◽  
Jiarui Li ◽  
Yong Cheng ◽  
...  
Keyword(s):  
Retinopathy Of Prematurity ◽  
Direct Sequencing ◽  
Clinical Manifestations ◽  
Retinal Disease ◽  
Chinese Patients ◽  
Missense Mutations ◽  
Genetical Analysis ◽  
Pathogenic Genes ◽  
Clinical Presentations ◽  
Comprehensive Health

Abstract Background Retinopathy of prematurity (ROP) is a multifactorial retinal disease, involving both environmental and genetic factors; The purpose of this study is to evaluate the clinical presentations and genetic variants in Chinese patients with ROP. Methods A total of 36 patients diagnosed with ROP were enrolled in this study, their medical and ophthalmic histories were obtained, and comprehensive clinical examinations were performed. Genomic DNA was isolated from peripheral blood of ROP patients, polymerase chain reaction and direct sequencing of the associated pathogenic genes (FZD4, TSPAN12, and NDP) were performed. Results All patients exhibited the clinical manifestations of ROP. No mutations were detected in the TSPAN12 and NDP genes in all patients; Interestingly, three novel missense mutations were identified in the FZD4 gene (p.A2P, p.L79M, and p.Y378C) in four patients, for a detection rate of 11.1% (4/36). Conclusions This study expands the genotypic spectrum of FZD4 gene in ROP patients, and our findings underscore the importance of obtaining molecular analyses and comprehensive health screening for this retinal disease.

scholarly journals MLH1 and MSH2 Gene Mutations and Polymorphisms in Six Malay Families with Hereditary Nonpolyposis Colorectal Cancer

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Wan Khairunnisa Wan Juhari ◽  
Khairul Bariah Ahmad Amin Noordin ◽  
Wan Faiziah Wan Abdul Rahman ◽  
Andee Dzulkarnaen Zakaria ◽  
Ahmad Shanwani Mohd Sidek ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Hereditary Nonpolyposis Colorectal Cancer ◽  
Direct Sequencing ◽  
Gene Mutations ◽  
Genetic Alterations ◽  
Missense Mutations ◽  
Nucleotide Polymorphisms ◽  
Msh2 Gene ◽  
Hereditary Nonpolyposis ◽  
The Impact

Background: Hereditary nonpolyposis colorectal cancer (HNPCC) also known as Lynch syndrome is commonly caused by genetic alterations in any of the four mismatch repair (MMR) genes; MLH1, MSH2, MSH6 and PMS2. This is the first study aimed to investigate genetic variants in Malay HNPCC families. Methods: Six Malay HNPCC families who fulfilled any of the Bethesda criteria were recruited into this study. A total of 3 ml of blood was withdrawn from each patient in the families. The samples were further analyzed using polymerase chain reaction and direct sequencing of the selected exons of MLH1 and MSH2 genes. Results: Two missense mutations and four single nucleotide polymorphisms (SNPs) were identified in six patients. These variants in the MLH1 and MSH2 genes were identified in four families who met the revised Bethesda guidelines. In two families, no mutation and polymorphism was identified in both the exon and intron of the respective genes. Of the mutations and polymorphisms identified, five have never been reported in Malay HNPCC families before. A missense mutation was detected in exon 5 of the MLH1 gene, c.394G>C (p.Asp132His) and four mutations and polymorphisms were detected in the MSH2 gene; heterozygous c.211+98T>C and c.211+9C>G and homozygous c.211+98T>C and c.211+9C>G, c.367-86A>C and c.382C>G. Conclusion: The results represented a new spectrum of mutations and polymorphisms in the Malay HNPCC families. However, a larger study involving additional families and analysis is required to determine the impact and nature of the identified mutations and polymorphisms.

scholarly journals SAMHD1Gene Mutations Are Associated with Cerebral Large-Artery Atherosclerosis

2015 ◽  
Vol 2015 ◽  
pp. 1-8
Author(s):  
Wei Li ◽  
Baozhong Xin ◽  
Junpeng Yan ◽  
Ying Wu ◽  
Bo Hu ◽  
...  
Keyword(s):  
Small Vessel Disease ◽  
Direct Sequencing ◽  
Gene Mutations ◽  
Splice Site Mutation ◽  
Large Artery ◽  
Missense Mutations ◽  
Site Mutation ◽  
Chinese Han ◽  
Functionally Impaired

Background. To investigate whether one or moreSAMHD1gene mutations are associated with cerebrovascular disease in the general population using a Chinese stroke cohort.Methods. Patients with a Chinese Han background (N=300) diagnosed with either cerebral large-artery atherosclerosis (LAA,n=100), cerebral small vessel disease (SVD,n=100), or other stroke-free neurological disorders (control,n=100) were recruited. Genomic DNA from the whole blood of each patient was isolated, and direct sequencing of theSAMHD1gene was performed. Both wild type and mutant SAMHD1 proteins identified from the patients were expressed inE. coliand purified; then their dNTPase activities and ability to form stable tetramers were analysedin vitro.Results. Three heterozygous mutations, including two missense mutations c.64C>T (P22S) and c.841G>A (p.E281K) and one splice site mutation c.696+2T>A, were identified in the LAA group with a prevalence of 3%. No mutations were found in the patients with SVD or the controls (p=0.05). The mutant SAMHD1 proteins were functionally impaired in terms of their catalytic activity as a dNTPase and ability to assemble stable tetramers.Conclusions. HeterozygousSAMHD1gene mutations might cause genetic predispositions that interact with other risk factors, resulting in increased vulnerability to stroke.

scholarly journals Identification of Novel ARSA Mutations in Chinese Patients with Metachromatic Leukodystrophy

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Li Chen ◽  
Huifang Yan ◽  
Binbin Cao ◽  
Ye Wu ◽  
Qiang Gu ◽  
...  
Keyword(s):  
Metachromatic Leukodystrophy ◽  
Direct Sequencing ◽  
Chinese Patients ◽  
Insertion Mutation ◽  
Inherited Disease ◽  
Wild Type ◽  
Novel Mutations ◽  
Genetic Characteristics ◽  
Developmental Problems ◽  
Polymerase Chain

Objective. Metachromatic leukodystrophy (MLD) is an inherited disease caused by a deficiency of the enzyme arylsulfatase A (ARSA) that leads to severe physiologic and developmental problems. Our study is aimed at elucidating the clinical and genetic characteristics of Chinese MLD patients. Methods. Clinical data of 21 MLD patients was collected. All coding exons of ARSA and their flanking intronic sequences were amplified by polymerase chain reaction and subjected to direct sequencing. Results. All 21 patients were diagnosed with MLD clinically and genetically, out of which 17 patients were late infantile and 4 were juvenile types. A total of 34 ARSA mutations, including 28 novel mutations (22 missense, 1 splicing, 1 nonsense, 3 small insertions, and 1 small deletion mutation) and 6 known mutations (5 missense and 1 small insertion mutation), were identified. Prenatal diagnosis was performed for four pedigrees. One fetus was a patient, two fetuses were carriers, and two were wild type. Conclusions. The present study discovered 28 novel ARSA mutations and widely expanded the mutation spectrum of ARSA. Four successful prenatal diagnoses provided critical information for MLD families.

scholarly journals Novel Norrie disease gene mutations in Chinese patients with familial exudative vitreoretinopathy

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Li-Yun Jia ◽  
Kai Ma
Keyword(s):  
Disease Gene ◽  
Direct Sequencing ◽  
Venous Blood ◽  
Gene Mutations ◽  
Chinese Patients ◽  
Control Group ◽  
Coding Region ◽  
Exon 2 ◽  
Norrie Disease ◽  
Familial Exudative Vitreoretinopathy

Abstract Purpose This study aims to analyze the Norrie disease gene (NDP) variants in patients with familial exudative vitreoretinopathy (FEVR) and their clinical features. Methods Thirty-three Chinese patients (22 familial and 11 simplex) who were diagnosed as FEVR underwent detailed ocular examinations in Beijing Tongren Hospital. Peripheral venous blood was drawn from the patients and their family members for the extraction of genomic DNA. All exons of NDP gene were analyzed by direct sequencing of PCR-amplified DNA fragments. Results Four novel mutations in NDP gene were identified in four X-linked FEVR families: a C → T transversion, c. 625C → T, in exon 3, resulting in a serine-to-proline change in codon 73 (S73P); a C → G transition, c. 751C → G, in exon 3, resulting in an arginine-to-glycine change in codon 115 (R115G); a T → C transversion of nucleotide 331 at 5’UTR in exon 2 (c.331 T → C); and a C → T transversion of the nucleotide 5 in intron 1 (IVS1 + 5C → T). The mutations were not present in the control group (n = 100). Conclusions Our results extend the spectrum of NDP gene mutations. The mutations in the non-coding region of NDP may play a crucial role in the pathogenesis of FEVR.

scholarly journals Four novel mutations in the ALPL gene in Chinese patients with odonto, childhood, and adult hypophosphatasia

2018 ◽  
Vol 38 (4) ◽  
Author(s):  
Lijun Xu ◽  
Qianqian Pang ◽  
Yan Jiang ◽  
Ou Wang ◽  
Mei Li ◽  
...  
Keyword(s):  
Serum Alkaline Phosphatase ◽  
Gene Mutations ◽  
Dominant Negative ◽  
Chinese Patients ◽  
Dominant Negative Effect ◽  
Healthy Controls ◽  
Missense Mutations ◽  
Genetic Characteristics ◽  
Chinese Families ◽  
Negative Effect

Hypophosphatasia (HPP) is a rare inherited disorder characterized by defective bone and/or dental mineralization, and decreased serum alkaline phosphatase (ALP) activity. ALPL, the only gene related with HPP, encodes tissue non-specific ALP (TNSALP). Few studies were carried out in ALPL gene mutations in the Chinese population with HPP. The purpose of the present study is to elucidate the clinical and genetic characteristics of HPP in five unrelated Chinese families and two sporadic patients. Ten clinically diagnosed HPP patients from five unrelated Chinese families and two sporadic patients and fifty healthy controls were genetically investigated. All 12 exons and exon–intron boundaries of the ALPL gene were amplified by PCR and directly sequenced. The laboratory and radiological investigations were conducted simultaneously in these HPP ten patients. A 3D model of the TNSALP was used to predict the dominant negative effect of identified missense mutations. Three odonto, three childhood, and four adult types of HPP were clinically diagnosed. Ten mutations were identified in five unrelated Chinese families and two sporadic patients, including eight missense mutations and two frameshift mutations. Of which, four were novel: one frameshift mutation (p.R138Pfsx45); three missense mutations (p.C201R, p.V459A, p.C497S). No identical mutations and any other new ALPL mutations were found in unrelated 50 healthy controls. Our study demonstrated that the ALPL gene mutations are responsible for HPP in these Chinese families. These findings will be useful for clinicians to improve understanding of this heritable bone disorder.

Analysis of NPM1 Gene Mutations in Chinese Adults with Acute Myeloid Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4503-4503
Author(s):  
De Pei Wu ◽  
Lingzhi Yan ◽  
Suning Chen ◽  
Jianying Liang ◽  
Yufeng Feng
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Direct Sequencing ◽  
Gene Mutations ◽  
Normal Karyotype ◽  
Chinese Patients ◽  
Chinese Adults ◽  
Cytoplasmic Transport ◽  
Acute Myeloid

Abstract Many European groups have described that mutations at exon-12 of the nucleophosmin (NPM1) gene are the most frequent genetic lesion in acute myeloid leukemia (AML) (45.7%~61.7% of all adult AMLs with normal karyotype). This outstanding discovery provides a promising minimal residual disease (MRD) marker for AMLs with normal karyotype. To clarify the prevalence and the clinical profile of NPM1 mutations in Chinese patients with AML, we analyzed a cohort of 156 newly diagnosed adult AMLs for this mutation. Genomic DNAs were prepared from bone marrow samples of these patients. NPM1 exon 12 mutations were detected using direct sequencing or fragment analysis of DNA-PCR products. NPM1 mutations were present in 28.2% of the overall population, including 1/1(100%) of M0, 11/27(40.7%) of M1, 11/46(23.9%) of M2, 0/29(0%) of M3, 2/9(22.2%) of M4, 18/39(46.2%) of M5 and 1/5(20.0%) of M6. NPM1 gene mutations were more prevalent in patients with a normal karyotype (37 of 90; 41.1%), when compared with patients with karyotypic abnormalities (7 of 66; 10.6%; P<0.001). Sequence analysis of 25 NPM1 mutated cases revealed known mutations (type A, B, NM, and PM) as well as 1 novel sequence variation (here named as type S). All mutational types were heterozygous and showed a 4 bp insertion between position nucleotide 960 and 961 (Genebank accession number: NM-002500). NPM1 mutations were significantly associated with old age (P<0.05), high peripheral white cell count (P<0.05) and FAB-M1/M5, but negatively associated with expression of CD34 (P<0.05) and CD117 (P<0.05). In conclusion, NPM1 mutations also represent a common genetic abnormality in Chinese adults with AML, especially in the presence of a normal karyotype. The occurrence of NPM1 mutations indicates an age-dependent characteristic. NPM1 mutated cases show a special clinical subtype of AML. Further studies are urgently needed to confirm the role of NPM1 mutations in leukemogenesis. The altered nucleo-cytoplasmic transport of NPM1 mutated protein is probably a potential therapic target for AML with NPM1 mutations.

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