scholarly journals Heterozygous FMN2 Missense Variant Found in A Family Case of Premature Ovarian Insufficiency

2021 ◽  
Author(s):  
Jie Li ◽  
Tianliu Peng ◽  
Le Wang ◽  
Panpan Long ◽  
Ruping Quan ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Low Frequency ◽  
Missense Variant ◽  
Sporadic Case ◽  
Premature Ovarian Insufficiency ◽  
Chinese Family ◽  
Ovarian Insufficiency ◽  
Mutant Type ◽  
Pathogenic Genes ◽  
Whole Exome

Abstract Background Premature Ovarian Insufficiency plagues 1% of women under 40, while quite a few remain an unknown cause. The development of sequencing has helped find pathogenic genes and reveal the relationship between DNA repair and ovarian reserve. Through the exome sequencing, our study targets screening out the possible POI pathogenic gene and variants in a Chinese family and 20 sporadic POI patients, preliminarily exploring the functional impact and finding out potential linkages between the gene and POI. Results The whole exome sequencing suggested a novel FMN2 heterozygous variant c.1949C > T (p.Ser650Leu) carried by all three patients in a Chinese family and another c.1967G > A(p.Arg656His) variant in a sporadic case. Since no FMN2 missense mutation is reported for causing human POI, we preliminarily assessed p.Ser650Leu variant via cross-species alignment and 3D modeling and found it possibly deleterious. A series of functional evidence was consistent with our hypothesis. We proved the expression of FMN2 in different stages of oocytes and observed a statistical difference of chromosomal breakages between the POI patient carrying p.Arg656His variant and the health control (p = 0.0013). Western Blot also suggested a decrease in FMN2 and P21 in the mutant type and an associated increase in H2AX. The p.Arg656His variant with an extremely low frequency also indicated that the gene FMN2 might play an essential role in the genetic etiology of POI. To the best of our knowledge, this is the first POI report on missense variants of FMN2. Conclusion This finding indicates a novel gene possibly related to POI and sheds lights on the study of FMN2.

scholarly journals Whole-exome sequencing identifies GPSM1 as a susceptibility gene for premature ovarian insufficiency

2020 ◽  
Author(s):  
Xuzi Cai ◽  
Huijiao Fu ◽  
Yan Wang ◽  
Qiwen Liu ◽  
Xuefeng Wang
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Caspase 3 ◽  
Susceptibility Gene ◽  
Primordial Follicle ◽  
Antral Follicle ◽  
Premature Ovarian Insufficiency ◽  
Protein Signaling ◽  
Ovarian Insufficiency ◽  
Whole Exome

Abstract Background Genetic causes of premature ovarian insufficiency (POI) account for approximately 20~25% of patients. So far, only a few genes have been identified. Results Here, we first identified the c.1840C>A on G-protein signaling modulator 1 (GPSM1) as a susceptibility locus for POI in 10 sporadic POI patients by whole-exome sequencing. The frequency of GPSM1 c.1840C>A was then verified as 3/20 in a POI sample of 20 patients (including the above 10 patients) by Sanger sequencing. RT-PCR and western blot analysis showed the expression of GPSM1 in rat ovaries was increased in the large antral follicle stage compared to the primordial follicle stage (P<0.01). The cell proliferation assay (CCK8) and flow cytometry suggested that the small-interfering RNA-induced silencing of Gpsm1 significantly increased apoptosis and decreased proliferation of rat ovarian granulosa cells (GCs) (P<0.01). Furthermore, suppression of Gpsm1 in GCs reduced levels of cAMP, PKAc, p-CREB as well as the ratio of Bcl-2/Bax, and increased the expression of Caspase-3 and Cleaved Caspase-3 (P<0.01). Conclusions In summary, this study identified a susceptibility variant GPSM1 c.1840C>A of POI for the first time. Gpsm1 was related to rat follicle development, and silencing increased apoptosis and decreased proliferation in rat GCs, possibly through inhibition of the cAMP-PKA-CREB pathway. These findings facilitate the development of the early molecular diagnosis of POI.

scholarly journals A Novel Missense Variant of TP63 Heterozygously Present in Split-Hand/Foot Malformation

2020 ◽  
Vol 2020 ◽  
pp. 1-5
Author(s):  
Hao Geng ◽  
Dongdong Tang ◽  
Chuan Xu ◽  
Xiaojin He ◽  
Zhiguo Zhang
Keyword(s):  
Blood Sample ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Peripheral Blood ◽  
Sanger Sequencing ◽  
Missense Variant ◽  
Chinese Family ◽  
Peripheral Blood Sample ◽  
Whole Exome ◽  
Novel Variant

Background. Split-hand/foot malformation (SHFM) is a severe congenital disability mainly characterized by the absence or hypoplasia of the central ray of the hand/foot. To date, several candidate genes associated with SHFM have been identified, including TP63, DLX5, DLX6, FGFR1, and WNT10B. Herein, we report a novel variant of TP63 heterozygously present in affected members of a family with SHFM. Methods. This study investigated a Chinese family, in which the proband and his son suffered from SHFM. The peripheral blood sample of the proband was used to perform whole-exome sequencing (WES) to explore the possible genetic causes of this disease. Postsequencing bioinformatic analyses and Sanger sequencing were conducted to verify the identified variants and parental origins on all family members in the pedigree. Results. By postsequencing bioinformatic analyses and Sanger sequencing, we identified a novel missense variant (NM_003722.4:c.948G>A; p.Met316Ile) of TP63 in this family that results in a substitution of methionine with isoleucine, which is probably associated with the occurrence of SHFM. Conclusion. A novel missense variant (NM_003722.4:c.948G>A; p.Met316Ile) of TP63 in SHFM was thus identified, which may enlarge the spectrum of known TP63 variants and also provide new approaches for genetic counselling of families with SHFM.

Whole-exome sequencing identifies a Novel SCN5A mutation (C335R) in a Chinese family with arrhythmia

2018 ◽  
Vol 28 (5) ◽  
pp. 688-691 ◽  
Author(s):  
Hao Huang ◽  
Dong-Bo Ding ◽  
Liang-Liang Fan ◽  
Jie-Yuan Jin ◽  
Jing-Jing Li ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Missense Mutation ◽  
Whole Exome Sequencing ◽  
Chinese Family ◽  
Illumina Hiseq ◽  
Α Subunit ◽  
Pathogenic Genes ◽  
Whole Exome ◽  
Gene Filtering ◽  
Protein Dysfunction

AbstractBackgroundSCN5A encodes sodium-channel α-subunit Nav1.5. The mutations of SCN5A can lead to hereditary cardiac arrhythmias such as the long-QT syndrome type 3 and Brugada syndrome. Here we sought to identify novel mutations in a family with arrhythmia.MethodsGenomic DNA was isolated from blood of the proband, who was diagnosed with atrial flutter. Illumina Hiseq 2000 whole-exome sequencing was performed and an arrhythmia-related gene-filtering strategy was used to analyse the pathogenic genes. Sanger sequencing was applied to verify the mutation co-segregated in the family.Results and conclusionsA novel missense mutation in SCN5A (C335R) was identified, and this mutation co-segregated within the affected family members. This missense mutation was predicted to result in amplitude reduction in peak Na+ current, further leading to channel protein dysfunction. Our study expands the spectrum of SCN5A mutations and contributes to genetic counselling of families with arrhythmia.

scholarly journals Whole-exome sequencing in patients with premature ovarian insufficiency: early detection and early intervention

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Hongli Liu ◽  
Xiaoli Wei ◽  
Yanwei Sha ◽  
Wensheng Liu ◽  
Haijie Gao ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Ovarian Function ◽  
In Silico Analysis ◽  
Premature Ovarian Insufficiency ◽  
Control Group ◽  
Genetic Etiology ◽  
Ovarian Insufficiency ◽  
Pathogenic Variants ◽  
Whole Exome

Abstract Background The loss of ovarian function in women, referred to as premature ovarian insufficiency (POI), is associated with a series of concomitant diseases. POI is genetically heterogeneous, and in most cases, the etiology is unknown. Methods Whole-exome sequencing (WES) was performed on DNA samples obtained from patients with POI, and Sanger sequencing was used to validate the detected potentially pathogenic variants. An in silico analysis was carried out to predict the pathogenicity of the variants. Results We recruited 24 patients with POI and identified variants in POI-related genes in 14 patients, including bi-allelic mutations in DNAH6, HFM1, EIF2B2, BNC, and LRPPRC and heterozygous variants in BNC1, EIF2B4, FOXL2, MCM9, FANCA, ATM, EIF2B3, and GHR. No variants in the above genes were detected in the WES data obtained from 29 women in a control group without POI. Determining a clear genetic etiology could significantly increase patient compliance with appropriate intervention strategies. Conclusions Our study confirmed that POI is a genetically heterogeneous condition and that whole-exome sequencing is a powerful tool for determining its genetic etiology. The results of this study will aid researchers and clinicians in genetic counseling and suggests the potential of WES for the detection of POI and thus early interventions for patients with POI.

scholarly journals Gene variants identified by whole-exome sequencing in 33 French women with premature ovarian insufficiency

2018 ◽  
Vol 36 (1) ◽  
pp. 39-45 ◽  
Author(s):  
Xiang Yang ◽  
Philippe Touraine ◽  
Swapna Desai ◽  
Gregory Humphreys ◽  
Huaiyang Jiang ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Premature Ovarian Insufficiency ◽  
Gene Variants ◽  
Ovarian Insufficiency ◽  
Whole Exome

Whole exome sequencing in monozygotic twins discordant for premature ovarian insufficiency

2015 ◽  
Vol 104 (3) ◽  
pp. e111
Author(s):  
N. Banks ◽  
A. Martinez ◽  
L. Brown ◽  
J. Hughes ◽  
A. DeCherney ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Monozygotic Twins ◽  
Premature Ovarian Insufficiency ◽  
Ovarian Insufficiency ◽  
Whole Exome

scholarly journals A novel pathogenic variant of IHH for Brachydactyly type A1

2019 ◽  
Author(s):  
Qi Yang ◽  
Jin Wang ◽  
Xiaoxian Tian ◽  
Fei Chen ◽  
Jing Lan ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Autosomal Dominant ◽  
Missense Variant ◽  
Specific Region ◽  
Chinese Family ◽  
Indian Hedgehog ◽  
Autosomal Dominant Disorder ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Active Fragment

Abstract Brachydactyly type A1 (BDA-1, MIM 112500) is a genetically heterogeneous autosomal-dominant disorder mainly characterized by shortening or missing of the middle phalanges. Brachydactyly type A1 (BDA-1) is caused by heterozygous pathogenic variants in a specific region of the N-terminal active fragment of Indian Hedgehog (IHH). In this study, we reported a Chinese family with 8 members affected with Brachydactyly type A1. After performing whole-exome sequencing in the proband, we identified a novel heterozygous missense variant c.299A>G (p.D100G) at the mutational hotspot of IHH gene. The variant co-segregated with BDA-1 in the pedigree, showed 100% penetrance for phalange phenotype with variable expressivity. This finding expanded the Brachydactyly type A1-related mutational spectrum of IHH gene.

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