scholarly journals Association of DNAH11 gene polymorphisms with asthenozoospermia in Northeast Chinese patients

2019 ◽  
Vol 39 (6) ◽  
Author(s):  
Dongliang Zhu ◽  
Hongguo Zhang ◽  
Ruixue Wang ◽  
Xiaojun Liu ◽  
Yuting Jiang ◽  
...  
Keyword(s):  
Male Infertility ◽  
Heavy Chain ◽  
In Silico Analysis ◽  
Chinese Patients ◽  
Compound Heterozygous ◽  
Respiratory Cilia ◽  
Increased Risk ◽  
Compound Heterozygous Variants ◽  
Targeted Gene Sequencing ◽  
High Degree

Abstract Summary: Reduced or no progressive sperm motility in the fresh ejaculate defines asthenozoospermia as one of the major causes of male infertility. The axonemal heavy chain dynein type 11 (DNAH11) gene encodes for one of the axonemal dynein heavy chain (DHC) family members and participates in assembling respiratory cilia and sperm flagella. Given the high degree of conservation of DNAH11, mutations could give rise to primary ciliary dyskinesia (PCD) and asthenozoospermia. To date, few studies have reported on the association between variants in DNAH11 and asthenozoospermia. In the present study, 87 patients with idiopathic asthenozoospermia for variants in DNAH11 were screened by using high-throughput targeted gene sequencing technology. Bioinformatics analysis was further assessed. We found compound heterozygous variants (c.9484-1 G>T, c.12428 T>C) of DNAH11 detected in 1 of 87 patients. The variant c.9484-1 G>T was confirmed as a novel virulence variant which was predicted to affect splicing by Human Splicing Finder 3.1. And c.12428 T>C was predicted to be mildly pathogenic in silico analysis. We found that DNAH11 polymorphisms display strong associations with asthenozoospermia, and may contribute to an increased risk of male infertility in Chinese patients.

scholarly journals Novel HSD17B4 Variants Cause Progressive Leukodystrophy in Childhood: Case Report and Literature Review

2021 ◽  
Vol 8 ◽  
pp. 2329048X2110486
Author(s):  
Akiyo Yamamoto ◽  
Shinobu Fukumura ◽  
Yumi Habata ◽  
Sachiko Miyamoto ◽  
Mitsuko Nakashima ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Brain Magnetic Resonance Imaging ◽  
Compound Heterozygous ◽  
Long Chain Fatty Acids ◽  
Developmental Regression ◽  
Whole Exome ◽  
Uncertain Significance ◽  
Compound Heterozygous Variants ◽  
High Degree ◽  
Moderate Hearing Loss

D-bifunctional protein (DBP) deficiency is a peroxisomal disorder with a high degree of phenotypic heterogeneity. Some patients with DBP deficiency develop progressive leukodystrophy in childhood. We report a 6-year-old boy with moderate hearing loss who presented with developmental regression. Brain magnetic resonance imaging demonstrated progressive leukodystrophy. However, very long chain fatty acids (VLCFAs) in the plasma were at normal levels. Whole-exome sequencing revealed compound heterozygous variants in HSD17B4 (NM_000414.3:c.[350A > T];[394C > T], p.[[Asp117Val]];[[Arg132Trp]]). The c.394C > T variant has been identified in patients with DBP deficiency and is classified as likely pathogenic, while the c.350A > T variant was novel and classified as uncertain significance. Although one of the two variants was classified as uncertain significance, an accumulation of phytanic and pristanic acids was identified in the patient, confirming type III DBP deficiency. DBP deficiency should be considered as a diagnosis in children with progressive leukodystrophy and hearing loss even if VLCFAs are within normal levels.

scholarly journals Mutations in the stromal antigen 3 (STAG3) gene cause male infertility due to meiotic arrest

2019 ◽  
Author(s):  
N van der Bijl ◽  
A Röpke ◽  
U Biswas ◽  
M Wöste ◽  
R Jessberger ◽  
...  
Keyword(s):  
Male Infertility ◽  
Germ Cells ◽  
Protein Function ◽  
Sanger Sequencing ◽  
Compound Heterozygous ◽  
Sequence Variants ◽  
Coding Region ◽  
Meiotic Arrest ◽  
Healthy Human ◽  
Compound Heterozygous Variants

Abstract STUDY QUESTION Are sequence variants in the stromal antigen 3 (STAG3) gene a cause for non-obstructive azoospermia (NOA) in infertile human males? SUMMARY ANSWER Sequence variants affecting protein function of STAG3 cause male infertility due to meiotic arrest. WHAT IS KNOWN ALREADY In both women and men, STAG3 encodes for a meiosis-specific protein that is crucial for the functionality of meiotic cohesin complexes. Sequence variants in STAG3 have been reported to cause meiotic arrest in male and female mice and premature ovarian failure in human females, but not in infertile human males so far. STUDY DESIGN, SIZE, DURATION The full coding region of STAG3 was sequenced directly in a cohort of 28 men with NOA due to meiotic arrest. In addition, a larger group of 275 infertile men that underwent whole-exome sequencing (WES) was screened for potential STAG3 sequence variants. Furthermore, meiotic spreads, immunohistochemistry, WES and population sampling probability (PSAP) have been conducted in the index case. PARTICIPANTS/MATERIALS, SETTING, METHODS This study included 28 infertile but otherwise healthy human males who underwent Sanger sequencing of the full coding region of STAG3. Additionally, WES data of 275 infertile human males with different infertility phenotypes have been screened for relevant STAG3 variants. All participants underwent karyotype analysis and azoospermia factor (AZF) screening in advance. In the index patient, segregation analysis, WES data, PSAP, lab parameters, testis histology and nuclear spreads have been added to suplort the findings. MAIN RESULTS AND THE ROLE OF CHANCE Two compound-heterozygous variants in STAG3 (c.[1262T>G];[1312C>T], p.[(Leu421Arg)];[(Arg438Ter)]) have been found to cause male infertility due to complete bilateral meiotic arrest in an otherwise healthy human male. Compound heterozygosity was confirmed by Sanger sequencing of the parents and the patient’s brother. Other variants which may affect spermatogenesis have been ruled out through analysis of the patient’s WES data and application of the PSAP pipeline. As expected from Stag3 knockout-mice meiotic spreads, germ cells did not develop further than zygotene and showed drastic chromosome aberrations. No rare variants in STAG3 were found in the 275 infertile males with other phenotypes. Our results indicate that STAG3 variants that negatively affect its protein function are a rare cause of NOA (<1% of cases). LIMITATIONS, REASONS FOR CAUTION We identified only one patient with compound-heterozygous variants in STAG3 causing NOA due to meiotic arrest. Future studies should evaluate STAG3 variants in larger cohorts to support this finding. WIDER IMPLICATIONS OF THE FINDINGS Identification of STAG3 sequence variants in infertile human males should improve genetic counselling as well as diagnostics and treatment. Especially before testicular sperm extraction (TESE) for ICSI, STAG3 variants should be ruled out to prevent unnecessary interventions with frustrating outcomes for both patients and clinicians. STUDY FUNDING/COMPETING INTEREST(S) This work was carried out within the frame of the German Research Foundation (DFG) Clinical Research Unit ‘Male Germ Cells: from Genes to Function’ (CRU326). Work in the laboratory of R.J. is supported by a grant of the European Union H2020 program GermAge. The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER Not applicable.

scholarly journals Novel Bi-Allelic Variants of FANCM Cause Sertoli Cell-Only Syndrome and Non-Obstructive Azoospermia

2021 ◽  
Vol 12 ◽  
Author(s):  
Yuxiang Zhang ◽  
Peng Li ◽  
Nachuan Liu ◽  
Tao Jing ◽  
Zhiyong Ji ◽  
...  
Keyword(s):  
Male Infertility ◽  
Sertoli Cell ◽  
Severe Disease ◽  
Sporadic Case ◽  
Compound Heterozygous ◽  
Obstructive Azoospermia ◽  
Core Complex ◽  
Allelic Variants ◽  
Interstrand Crosslink ◽  
Compound Heterozygous Variants

Non-obstructive azoospermia (NOA) is the most severe disease in male infertility, but the genetic causes for the majority of NOA remain unknown. FANCM is a member of Fanconi Anemia (FA) core complex, whose defects are associated with cell hypersensitivity to DNA interstrand crosslink (ICL)-inducing agents. It was reported that variants in FANCM (MIM: 609644) might cause azoospermia or oligospermia. However, there is still a lack of evidence to explain the association between different FANCM variants and male infertility phenotypes. Herein, we identified compound heterozygous variants in FANCM in two NOA-affected brothers (c. 1778delG:p. R593Qfs*76 and c. 1663G &gt; T:p. V555F), and a homozygous variant in FANCM (c. 1972C &gt; T:p. R658X) in a sporadic case with NOA, respectively. H&amp;E staining and immunohistochemistry showed Sertoli cell-only Syndrome (SCOS) in the three patients with NOA. Collectively, our study expands the knowledge of variants in FANCM, and provides a new insight to understand the genetic etiology of NOA.

scholarly journals XRCC5 VNTR, XRCC6 -61C>G, and XRCC7 6721G>T Gene Polymorphisms Associated with Male Infertility Risk: Evidences from Case-Control and In Silico Studies

2017 ◽  
Vol 2017 ◽  
pp. 1-16 ◽  
Author(s):  
Danial Jahantigh ◽  
Abasalt Hosseinzadeh Colagar
Keyword(s):  
Male Infertility ◽  
In Silico ◽  
Gene Polymorphisms ◽  
Tandem Repeats ◽  
In Silico Analysis ◽  
Severe Oligozoospermia ◽  
Nuclear Factors ◽  
Increased Risk ◽  
In Silico Studies ◽  
Increased Susceptibility

We evaluate the association between genetic polymorphisms of XRCC5 VNTR, XRCC6 -61C>G, and XRCC7 6721G>T with male infertility susceptibility. A total of 392 men including 178 infertile males (102 idiopathic azoospermia and 76 severe oligozoospermia) and 214 healthy controls were recruited. XRCC6 -61C>G and XRCC7 6721G>T genotyping was performed by PCR-RFLP whereas XRCC5 VNTR was performed by PCR. The 2R allele and 2R allele carriers of XRCC5 VNTR polymorphism significantly decreased risk of male infertility. The mutant GG genotypes and carriers of the CG and GG genotypes of XRCC6 -61C>G showed increased risk for the male infertility. Furthermore, the G allele of the XRCC6 -61C>G was correlated with increased susceptibility to male infertility. Likewise, the T allele of the XRCC7 6721G>T polymorphism was associated with increased susceptibility to male infertility in azoospermia. In silico analysis predicted that the presence of tandem repeats in XRCC5 gene prompter can be sequence to bind to more nuclear factors. Also, rs2267437 (C>G) variant was located in a well-conserved region in XRCC6 promoter and this variation might lead to differential allelic expression. The XRCC7 6721G>T gene polymorphism occurred in an acceptor-splicing site, but this polymorphism has no severe modification on XRCC7 mRNA splicing. Our results indicate the association of XRCC5 VNTR, XRCC6 -61C>G, and XRCC7 6721G>T gene polymorphisms with male infertility in Iranian men.

scholarly journals A Case Report of Germline Compound Heterozygous Mutations in the BRCA1 Gene of an Ovarian and Breast Cancer Patient

2021 ◽  
Vol 22 (2) ◽  
pp. 889
Author(s):  
Ava Kwong ◽  
Cecilia Y. S. Ho ◽  
Vivian Y. Shin ◽  
Chun Hang Au ◽  
Tsun Leung Chan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Brca1 Gene ◽  
Pathogenic Mutation ◽  
Compound Heterozygous ◽  
Strong Family History ◽  
Breast And Ovarian Cancer ◽  
Pathogenic Mutations ◽  
Increased Risk ◽  
History Of

The germline carrier of the BRCA1 pathogenic mutation has been well proven to confer an increased risk of breast and ovarian cancer. Despite BRCA1 biallelic pathogenic mutations being extremely rare, they have been reported to be embryonically lethal or to cause Fanconi anemia (FA). Here we describe a patient who was a 48-year-old female identified with biallelic pathogenic mutations of the BRCA1 gene, with no or very subtle FA-features. She was diagnosed with ovarian cancer and breast cancer at the ages of 43 and 44 and had a strong family history of breast and gynecological cancers.

scholarly journals Novel ARG1 variants identified in a patient with arginase 1 deficiency

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Katsuyuki Yokoi ◽  
Yoko Nakajima ◽  
Toshihiro Yasui ◽  
Makoto Yoshino ◽  
Tetsushi Yoshikawa ◽  
...  
Keyword(s):  
Sanger Sequencing ◽  
Arginase Activity ◽  
Compound Heterozygous ◽  
Measurement Sensitivity ◽  
Protein Core ◽  
Arginase 1 ◽  
Conserved Domain ◽  
New Variant ◽  
Compound Heterozygous Variants

AbstractWe report a case of a 13-year-old boy with arginase 1 deficiency carrying a new variant in ARG1. Sanger sequencing identified the compound heterozygous variants: NM_000045.4: c.365G>A (p.Trp122*)/c.820G>A (p.Asp274Asn). Although not previously reported, the p.Asp274Asn variant is predicted to have strong pathogenicity because it is located in a highly conserved domain in the protein core and arginase activity in the patient was below measurement sensitivity.

scholarly journals Intermittent concurrent use of clopidogrel and proton pump inhibitors did not increase risk of adverse clinical outcomes in Chinese patients with coronary artery disease

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Wanbing He ◽  
Xiaorong Shu ◽  
Enyi Zhu ◽  
Bingqing Deng ◽  
Yongqing Lin ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Proton Pump Inhibitors ◽  
Proton Pump ◽  
Cox Regression ◽  
Asian Population ◽  
Chinese Patients ◽  
Clinical Event ◽  
Cardiac Events ◽  
Concurrent Use ◽  
Increased Risk

Abstract Background Proton pump inhibitors (PPIs) are frequently prescribed to patients with coronary heart disease (CHD) under antiplatelet therapy to prevent gastrointestinal (GI) bleeding. However, its clinical impact is still under debate, especially in Asian population. This study was undertaken to explore the effects of concurrent use of clopidogrel and PPIs on the clinical outcomes in Chinese patients with CHD in secondary prevention. Methods A single-center retrospective study was conducted in 638 patients with CHD on consecutive clopidogrel therapy for at least 1 year. After 18-month follow-up, adverse clinical events were collected. Cox regression was used to calculate hazard ratios (HR) and 95% confidence interval (CI) for the effect of PPI use on the outcomes. A total of 638 patients were recruited from 2014 to 2015 in this study, among whom 201 were sustained PPI users, 188 were intermittent PPI users and the remaining 249 were non-PPI users. Results Compared with sustained PPI users, intermittent use of PPIs was associated with a lower risk of stroke, major adverse cardiac events (MACE) and net adverse clinical event (NACE) (stroke: adjusted HR: 0.109, 95% CI 0.014–0.878, p = 0.037; MACE: adjusted HR: 0.293, 95% CI 0.119–0.722; p = 0.008; NACE: adjusted HR: 0.357, 95% CI 0.162–0.786, p = 0.011). Subgroup analysis further revealed the benefit of intermittent PPI use was significant in male CHD patients over 60 years old, with hypertension or chronic kidney disease, and undergoing percutaneous coronary intervention during hospitalization. Conclusion The current findings suggest that the intermittent concurrent use of PPIs and clopidogrel is not associated with an increased risk of 18-month adverse clinical outcomes, and intermittent use of PPIs is associated with a lower rate of MACE and NACE.

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