scholarly journals Identification of Novel Mutation Sites in DNAH1 of Multiple Morphological Anomalies of the Flagella Patients

2021 ◽  
Author(s):  
Xiong Wang ◽  
Yan-Wei Sha ◽  
Xing-shen Zhu ◽  
Xiao-ya Zhang ◽  
Yuan-qing Cui ◽  
...  
Keyword(s):  
Intracytoplasmic Sperm Injection ◽  
Novel Mutation ◽  
Gene Mutations ◽  
The Body ◽  
Compound Heterozygous ◽  
Homozygous Mutation ◽  
Novel Mutations ◽  
Genetic Landscape ◽  
Morphological Anomalies ◽  
The Impact

Abstract BackgroundMultiple morphological anomalies of the sperm flagella (MMAF) is a term used to describe abnormalities in sperm morphology, which lead to primary infertility in males. Intracytoplasmic sperm injection (ICSI) is an effective treatment for MMAF. However, ICSI failure rates remain high in MMAF patients. Our purpose was to investigate novel gene mutations in a cohort of nineteen patients with MMAF and assess the impact of these mutations on assisted reproductive therapy.MethodsWe recruited nineteen infertile patients with MMAF and twenty healthy men with proven fertility at the Affiliated Yantai Yuhuangding Hospital of Qingdao University. The morphology of the spermatozoa was observed using Papanicolaou staining and the ultrastructure of the spermatozoa was inspected using transmission electron microscopy. Gene mutations were evaluated using whole-exome sequencing and novel mutations were further validated in patients and their parents using Sanger sequencing. The effect of these novel mutation sites on the expression of DNAH1 was analysed using immunofluorescence, and the effect of these novel mutations on pregnancy outcome was analysed using intracytoplasmic sperm injection (ICSI). ResultsSpermatozoa from 19 patients presented with a typical MMAF phenotype including severe ultrastructural defects. We identified ten novel mutation sites in the DNAH1 locus from six of these patients, none of which were identified in DNAH1 or the other MMAF-related genes from the twenty men with proven fertility. In the sperm from these patients, DNAH1 was absent. Three patients with DNAH1 mutation who underwent intracytoplasmic sperm injection (ICSI) had a good outcome. ConclusionHere, we describe several novel compound heterozygous mutations and a novel homozygous mutation in DNAH1 from six independent MMAF patients. This study adds to the body of knowledge surrounding the genetic landscape of MMAF and DNAH1 improving our ability to diagnose and treat MMAF efficiently.

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 BETA-GLOBIN GENE MUTATIONS IN TURKISH CHILDREN WITH BETA-THALASSEMIA: RESULTS FROM A SINGLE CENTER STUDY

2013 ◽  
Vol 5 (1) ◽  
pp. e2013055 ◽  
Author(s):  
Ali Fettah ◽  
Cengiz Bayram ◽  
Nese Yarali ◽  
Pamir Isik ◽  
Abdurrahman Kara ◽  
...  
Keyword(s):  
Globin Gene ◽  
Gene Mutations ◽  
Thalassemia Major ◽  
Compound Heterozygous Mutation ◽  
Heterozygous Mutation ◽  
Compound Heterozygous ◽  
Homozygous Mutation ◽  
Thalassemia Intermedia ◽  
Turkish Children ◽  
Tertiary Center

Introduction: The beta thalassemias are common genetic disorders in Turkey and in this retrospective study our aim was to evaluate β-globin chain mutations and the phenotypic severity of β-thalassemia patients followed-up in our hospital, a tertiary center which serves patients from all regions of Turkey. Materials and Methods: 106 pediatric patients were analysed for β-globin gene mutations by using DNA analysis. Patients were classified as having β-thalassemia major or β-thalassemia intermedia based on age at diagnosis, transfusion frequency and lowest hemoglobin concentration in between transfusions. Results: There were 106 patients (52.8% female and 47.2% male) with a mean age of 11.2±5 years (1.6 – 22.3 years). Eighty-four (79.2%) patients had β-thalassemia major, whereas the remaining 22 patients (20.8%) were identified as having β-thalassemia intermedia. Overall, 18 different mutations were detected on 212 alleles. The most frequently encountered mutation was IVS I.110 (G>A) (35.3%), followed by Codon 8 del-AA (10.4%), IVS II.1 (G>A) (8%), IVS I.1 (G>A) (7.5%), Codon 39 (C>T) (7.1%) and Codon 5 (-CT) (6.6%), which made up 79.4% of observed mutations. According to present results, IVS I.110 (G>AA) was the most frequent mutation observed in this study, as in other results from Turkey. Evaluation of β-thalassemia mutations in 106 patients with 212 alleles, revealed the presence of homozygous mutation in 85 patients (80.2%) and compound heterozygous mutation in 21 patients (19.8%). The mutations detected in patients with homozygous mutation were IVS I.110 (G>A) (38.8%), Codon 8 del –AA (11.8%), IVS II.1 (G>A) (8.2%) and IVS I.1 (G>A) (8.2%). Observed mutations in the compound heterozygotes were Codon 39 (C>T)/Codon 41-42 (-CTTT) (14.3%), IVS I.110 (G>A)/Codon 39(C>T) (14.3%), IVS I.110 (G>A)/Codon 44(-C) (14.3%), and IVS II.745 (C>G)/ 5’UTR + 22 (G>A) (9.5%). Conclusion: Our hospital is a tertiary referral center that provides care to patients from all over the country, and thus the distribution of mutations observed in the current study is significant in term of representing that of the country as a whole.

scholarly journals A Novel RFXANK Mutation in a Chinese Child With MHC II Deficiency: Case Report and Literature Review

2020 ◽  
Vol 7 (8) ◽  
Author(s):  
Yu Qing Cai ◽  
HangHu Zhang ◽  
Xiang Zhi Wang ◽  
ChengYun Xu ◽  
Yun Qi Chao ◽  
...  
Keyword(s):  
Case Report ◽  
Mhc Class Ii ◽  
Novel Mutation ◽  
Gene Mutations ◽  
Class Ii ◽  
Homozygous Mutation ◽  
Primary Immunodeficiency Disorder ◽  
Mhc Ii ◽  
First Case ◽  
Rfxank Gene

Abstract Major histocompatibility complex (MHC) II deficiency is a rare primary immunodeficiency disorder that is characterized by the deficiency of MHC class II molecules. The disease is caused by transcription factor mutations including class II transactivator (CIITA), regulatory factor X-5 (RFX5), RFX-associated protein (RFXAP), and RFXAP-containing ankyrin repeat (RFXANK), respectively. Mutations in the RFXANK gene account for >70% of all known patients worldwide. Herein, we reported a 10-month-old boy with MHC II deficiency caused by a novel mutation in the RFXANK gene (c.337 + 1G>C). The boy was admitted to the hospital due to pneumonia and diarrhea at 4 months of age. Genetic analysis revealed a novel homozygous mutation in the RFXANK gene, which derived from the c.337 + 1G>C heterozygous mutations in the RFXANK gene of his parents. The boy died 3 months after diagnosis. More than 200 cases have been reported, and a review of the literature revealed different mutation rates of 4 transcription factors in different countries or regions. This is the first case report of MHC II deficiency from East Asia. We also describe all gene mutations that cause MHC II deficiency and the epidemiology of MHC II deficiency with gene mutations in this paper.

scholarly journals Novel Mutations and Mutation Combinations ofTMPRSS3Cause Various Phenotypes in One Chinese Family with Autosomal Recessive Hearing Impairment

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
Xue Gao ◽  
Yong-Yi Yuan ◽  
Guo-Jian Wang ◽  
Jin-Cao Xu ◽  
Yu Su ◽  
...  
Keyword(s):  
Hearing Impairment ◽  
Autosomal Recessive ◽  
Novel Mutation ◽  
Chinese Family ◽  
Compound Heterozygous ◽  
Novel Mutations ◽  
Pathogenic Mutations ◽  
Compound Heterozygous Mutations

Autosomal recessive hearing impairment with postlingual onset is rare. Exceptions are caused by mutations in theTMPRSS3gene, which can lead to prelingual (DFNB10) as well as postlingual deafness (DFNB8).TMPRSS3mutations can be classified as mild or severe, and the phenotype is dependent on the combination ofTMPRSS3mutations. The combination of two severe mutations leads to profound hearing impairment with a prelingual onset, whereas severe mutations in combination with milderTMPRSS3mutations lead to a milder phenotype with postlingual onset. We characterized a Chinese family (number FH1523) with not only prelingual but also postlingual hearing impairment. Three mutations inTMPRSS3, one novel mutation c.36delC [p.(Phe13Serfs⁎12)], and two previously reported pathogenic mutations, c.916G>A (p.Ala306Thr) and c.316C>T (p.Arg106Cys), were identified. Compound heterozygous mutations of p.(Phe13Serfs⁎12) and p.Ala306Thr manifest as prelingual, profound hearing impairment in the patient (IV: 1), whereas the combination of p.Arg106Cys and p.Ala306Thr manifests as postlingual, milder hearing impairment in the patient (II: 2, II: 3, II: 5), suggesting that p.Arg106Cys mutation has a milder effect than p.(Phe13Serfs⁎12). We concluded that different combinations ofTMPRSS3mutations led to different hearing impairment phenotypes (DFNB8/DFNB10) in this family.

Compound Heterozygosity for a Novel Mutation Combined with G Insertion in Exon 13 Causes Severe Factor XI Deficiency in Patients of Japanese Origin.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4087-4087
Author(s):  
Nobutsune Ishikawa ◽  
Shinichiro Yasunaga ◽  
Motoaki Ohtsubo ◽  
Yoshihiro Takihara ◽  
Takashi Sato ◽  
...  
Keyword(s):  
Catalytic Domain ◽  
Novel Mutation ◽  
Gene Mutations ◽  
Compound Heterozygous ◽  
Type I ◽  
Ashkenazi Jews ◽  
Factor Xi ◽  
Inherited Disorders ◽  
Factor Xi Deficiency ◽  
Prolonged Aptt

Abstract Factor XI (FXI) deficiency is a rare autosomal recessive coagulopathy. However, it is one of the most common inherited disorders among Ashkenazi Jews. FXI deficiency is characterized by undetectable levels of FXI antigen and coagulant activity. Patients with FXI deficiency usually suffered from mild to moderate bleeding manifestations. Up to now, more than 80 gene mutations responsible for FXI deficiency have been reported including three common mutations (Type I, II and III) in Ashkenazi Jews. However, it has been reported that significantly higher frequency of allelic heterogeneity has been observed in different ethnic groups. We have studied the molecular basis of this disease in a Japanese family. Two children with FXI deficiency who are siblings have frequent epistaxis. Blood coagulation tests showed severely prolonged aPTT with normal PT. FXI coagulant activities of both patients were less than 1% activity. Their father and mother had normal aPTT, but the activities of FXI in parents showed 45% and 52% activities, respectively. Prolonged aPTT restored to normal range by the addition of recombinant Factor VIIa (NovoSevenR) dose-dependently, indicating the possible efficacy for the replacement therapy in this disorder. FXI gene mutations were screened by a PCR. We identified a novel mutation, C to G transversion in exon 12 in the FXI gene. The C to G transversion in exon 12 results in a missense mutaion (Q433E). That leads to the disruption of catalytic domain structure of FXI molecule. Another mutation was found in G insertion in exon 13, which was previously reported in only one Japanese patient, causes the frameshift, resulting in substitution of last 105 amino acids (Tyr503-Val607) with 32 abnormal amino acid residues. This change also induces the destruction of the catalytic domain of FXI. Thus, the compound heterozygous novel mutations found in Japanese are not identical to those in Ashkenazi Jews, suggesting that this mutation may not be of the same ancestry.

A novel DCAF17 homozygous mutation in a girl with Woodhouse-Sakati syndrome and review of the current literature

2019 ◽  
Vol 32 (11) ◽  
pp. 1287-1293 ◽  
Author(s):  
Erdal Kurnaz ◽  
Ayberk Türkyılmaz ◽  
Oğuzhan Yaralı ◽  
Berrin Demir ◽  
Atilla Çayır
Keyword(s):  
Neurological Disorders ◽  
Novel Mutation ◽  
Present Report ◽  
Clinical Findings ◽  
Breast Development ◽  
Compound Heterozygous ◽  
Homozygous Mutation ◽  
Whole Exome ◽  
Multisystemic Disease ◽  
Loss Of Hearing

Abstract Background Woodhouse-Sakati syndrome (WSS) (OMIM#241080) is an extremely rare multisystemic disease. Alopecia, hypogonadism, loss of hearing, hypothyroidism, diabetes mellitus (DM) and neurological disorders are the components of this syndrome. The syndrome is caused by homozygous or compound heterozygous mutations in DCAF17, and has recently been implicated in the development of both male and female gonads, thus resulting in hypogonadism. Case report A 16-year-old girl with consanguineous parents was admitted to our hospital with absence of breast development and amenorrhea. Hypogonadism was detected, in the form of hypergonadotropic hypogonadism. Whole-exome sequencing was used to identify the genetic etiology underlying the hypogonadism. A novel homozygous variant c.1091 + 1G > A was detected in DCAF17. Both parents were sequenced and identified as heterozygous for the same mutation. Conclusions We report a novel mutation detected in the DCAF17 gene and discuss the clinical findings in patients with previously reported mutations. Various manifestations of WSS, such as alopecia, endocrinological and neurological disorders, do not emerge until later in life, and therefore this situation can be challenging to diagnose particularly in pediatric cases, as in the present report. Careful attention should be paid to these additional findings, which may lead to early diagnosis and reduced genetic analysis costs, in patients with hypogonadism. In addition, there was no obvious genetic-phenotype correlation in reported cases.

scholarly journals Novel SCN1A and GABRA1 Gene Mutations With Diverse Phenotypic Features and the Question on the Existence of a Broader Spectrum of Dravet Syndrome

2017 ◽  
Vol 4 ◽  
pp. 2329048X1770679 ◽  
Author(s):  
Maria P. Gontika ◽  
Christopher Konialis ◽  
Constantine Pangalos ◽  
Antigone Papavasiliou
Keyword(s):  
Sodium Channel ◽  
Novel Mutation ◽  
Gene Mutations ◽  
Aminobutyric Acid ◽  
Dravet Syndrome ◽  
Review Of The Literature ◽  
Subunit Gene ◽  
Novel Mutations ◽  
Whole Exome ◽  
Α1 Subunit

In the light of modern molecular technologies, the understanding of the complexity of the numerous genotype–phenotype correlations regarding Dravet syndrome is mandatory. Motivated by 2 patients, whose whole-exome sequencing revealed novel mutations that exemplify the phenotypic and genetic heterogeneities associated with typical and atypical Dravet syndrome presentations, the authors discuss the existence of a broader spectrum of Dravet syndrome. The first patient is a 4-year-old boy with fairly typical Dravet syndrome and a novel sodium channel α1 subunit gene mutation of high-predicted combined pathogenicity likelihood. The second patient is a 15-year-old boy with some atypical features of Dravet syndrome, harboring a novel mutation of the γ-aminobutyric acid receptor α1 subunit gene, whose role in this syndrome pathogenesis has recently been highlighted. A brief review of the literature reveals that none of the current diagnostic criteria is thoroughly predictive of the disease, and phenotypic discrepancies are common among patients carrying atypical Dravet syndrome mutations. The authors conclude that the discussion of a Dravet syndrome spectrum is relevant.

scholarly journals Clinical Characteristics and Gene Mutation Analysis of the Chinese Han Population with Gitelman Syndrome: 3 Case Reports and a Literature Review

2020 ◽  
Vol 2020 ◽  
pp. 1-6
Author(s):  
Xueting Li ◽  
Ruofei Chen ◽  
Mingwei Chen
Keyword(s):  
Gene Mutation ◽  
Mutation Analysis ◽  
Clinical Characteristics ◽  
Clinical Phenotype ◽  
Gene Mutations ◽  
Gitelman Syndrome ◽  
Chinese Patients ◽  
Compound Heterozygous ◽  
Homozygous Mutation ◽  
Gene Mutation Analysis

The present study reported clinical characteristics and the results of gene mutation analysis of 3 Chinese patients with Gitelman syndrome (GS). Three patients manifested with normal blood pressure, recurrent hypokalemia, and metabolic alkalosis. Only case 2 had obvious hypomagnesemia. Gene sequencing showed a compound heterozygous mutation in SCL12A3 in case 1 and a homozygous mutation in SCL12A3 in case 2. Heterozygous mutations in SCL12A3 and CLCNKB were found in case 3. Then, the literature was reviewed. The keyword “Gitelman syndrome” was inputted into the PubMed, Wanfang Database, and CNK to search all Chinese patients with GS diagnosed by gene mutations and to extract complete clinical data from December 1998 to 2018. Finally, a total of 124 cases of GS were included. No significant differences in the levels of serum potassium and magnesium were observed among the different gene mutations, and the serum magnesium levels in adults were lower than those of the juvenile. GS with reduced blood magnesium had a serious clinical phenotype. Therefore, GS had a diverse phenotype, and its final diagnosis required genetic profiling. The relationship of gene mutation and clinical phenotype needed further study.

scholarly journals Identification of missense mutations of the KCNJ5 gene on patients suffering from aldosterone-production adenomas in adrenal cortex

2016 ◽  
Vol 14 (1) ◽  
pp. 15-21
Author(s):  
Lê Bắc Việt ◽  
Hoàng Thị Lan ◽  
Lương Thị Lan Anh ◽  
Nguyễn Huy Hoàng
Keyword(s):  
Adrenal Gland ◽  
Primary Aldosteronism ◽  
Structural Model ◽  
Novel Mutation ◽  
The Body ◽  
Heterozygous Mutation ◽  
Endocrine Disorders ◽  
Homozygous Mutation ◽  
Missense Mutations ◽  
Aldosterone Production

Aldosterone is an important hormone in the adrenal gland as well as the human body. It is responsible for regulating salt and water in the body, therefore controlling blood pressure. Primary aldosteronism (also known as aldosterone producing while suppressing renin) plays a significant role in the pathophysiology of hypertension. Mutation in the KCNJ5 gene which leads to aldosterone-production adenomas is the main cause of primary aldosteronism. In this study, the entire coding sequence of the KCNJ5 gene including 2 exons was amplified and directly sequenced to detect mutations. The result revealed that two missense mutations were identified in two patients with hypertension and an apparent mass on the adrenal gland. A heterozygous mutation, D223V, is a novel mutation while the homozygous mutation, Q282E, was known as a polymorphism that had a significant effect on viability of the H295R cell line and K+ conduction channel. Analysis of the 3D protein structural model of the mutants clarified the relationship between genotype and phenotype of the two patients. These results partially pointed out causes of the adrenal gland adenomas and endocrine disorders in the the patient.

Novel Mutations in Types 2 & 3 von Willebrand Disease and Correlation with von Willebrand Factor Multimer Patterns.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2136-2136 ◽  
Author(s):  
Ruetima Titapiwatanakun ◽  
Jennifer C. Guenther ◽  
Yan W. Asmann ◽  
Todd M. Daniels ◽  
John A. Heit ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Banding Pattern ◽  
Infrared Imaging ◽  
Imaging System ◽  
Novel Mutation ◽  
Von Willebrand Disease ◽  
Compound Heterozygous ◽  
Novel Mutations ◽  
Type 3 ◽  
Von Willebrand

Abstract Background & Objectives: Diagnosis and classification of VWD are currently based on integration of personal and family bleeding histories and results of protein-based diagnostic tests (VWF:Ag, VWF:RCo, FVIII:C, VWF:CB and VWF multimers) which have performance limitations. Genetic testing is emerging as a complementary diagnostic tool. We have identified mutations and correlated VWF multimer patterns in our patients (pt) with types 2 & 3 VWD, and report novel candidate mutations. Patients & Methods: Unrelated pt with type 3 (n=6) and subtypes 2 (n=22) VWD, from Mayo Comprehensive Hemophilia Center, consented to this IRB approved study. PCR amplification, from genomic DNA, of VWF gene (splice junctions, coding and promoter regions), avoiding pseudogene amplification, followed by ABI® sequencing and analysis (Mutation Surveyor: SoftGenetic®) were performed. Mutations were compared to VWD (ISTH), NCBI NR nucleotide and DV SNP databases. Comparison with available VWF sequences from other vertebrate species was performed. Selected regions not known to contain mutations remain to be sequenced. VWF multimer analysis was performed using a novel in-gel immunostaining and infrared imaging system. Results: Type 2A VWD (n=10), a novel mutation in exon 28 (E28) (V1524G: 2 pt) with characteristic VWF multimer abnormalities (decreased HMWM, increased satellite banding, suggesting enhanced VWF proteolysis). Type 2B VWD (n=6), 2 pt were compound heterozygous for 2 previously reported mutations, the first in E28 (R1306W)/E48 (T2647M) and the second in E28 (V1316M)/E20 (R854Q). Type 2M VWD (n=4): an 84 yr female with personal (spontaneous and post-surgical) and family bleeding histories, VWF:RCo 72%, VWF:Ag 118% (RCo:Ag ratio 0.61), normal FVIII and platelets, and aberrant VWF multimer banding pattern without substantive reduction of HMWM, had a novel mutation in E52 (S2775C; conserved in mouse, rat, chicken and dog); a 14 yr female with a history of bleeding, VWF:RCo 34%, VWF:Ag 68% (RCo:Ag ratio 0.5) and normal FVIII and platelets, was compound heterozygous for a known mutation (R1399C subtype not classified in VWD database) and two novel mutations: E30 (P1725S) (conserved in mouse, rat, dog, cow and chimp) & E49 (T2666M) (conserved in mouse, dog, rat not in chicken). VWF multimers demonstrated abnormal banding pattern without substantive reduction of HMWM; 2 unrelated pt and families with ultra-large and smeary multimers, previously classified as Vicenza variant, had R1374C mutations and were reclassified as Type 2M VWD. Type 2N VWD (n=1) previously reported mutation E20 (R854Q) was confirmed. Type 3 VWD, 2 pt had novel mutations, the first in E22 (E950X) and the second was a compound heterozygote for E43 (R2478Q)/E40 (E2322V) mutations. In general, patients with similar mutations had similar multimer patterns. Conclusions: We report novel candidate mutations in types 2 & 3 VWD and demonstrate novel VWF multimer patterns with our in-gel staining system. Multimer patterns correlated well with the underlying genotype. The novel mutations are likely causative, given their occurrence at highly conserved residues, but this needs to be confirmed with expression studies. Integration of genetic testing into the diagnostic workup of VWD will potentially lead to more accurate diagnosis and subtyping of VWD, and may further refine protein based testing and provide additional biological insight into VWD.

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