Whole exome sequencing in monozygotic twins discordant for premature ovarian insufficiency

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.

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Whole-exome sequencing reveals SALL4 variants in premature ovarian insufficiency: an update on genotype–phenotype correlations

Human Genetics ◽

10.1007/s00439-018-1962-4 ◽

2019 ◽

Vol 138 (1) ◽

pp. 83-92 ◽

Cited By ~ 7

Author(s):

Qiqi Wang ◽

Da Li ◽

Baozhu Cai ◽

Qing Chen ◽

Caihua Li ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Premature Ovarian Insufficiency ◽

Ovarian Insufficiency ◽

Whole Exome

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

Journal of Ovarian Research ◽

10.1186/s13048-020-00716-6 ◽

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.

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

Journal of Assisted Reproduction and Genetics ◽

10.1007/s10815-018-1349-4 ◽

2018 ◽

Vol 36 (1) ◽

pp. 39-45 ◽

Cited By ~ 6

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

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A novel EIF4ENIF1 mutation associated with a diminished ovarian reserve and premature ovarian insufficiency identified by whole-exome sequencing

Journal of Ovarian Research ◽

10.1186/s13048-019-0595-0 ◽

2019 ◽

Vol 12 (1) ◽

Cited By ~ 2

Author(s):

Minying Zhao ◽

Fan Feng ◽

Chunfang Chu ◽

Wentao Yue ◽

Lin Li

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Ovarian Reserve ◽

Diminished Ovarian Reserve ◽

Premature Ovarian Insufficiency ◽

Ovarian Insufficiency ◽

Whole Exome

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AIMP1 Mutation Long-Term Follow-Up, With Decreased Brain N-Acetylaspartic Acid and Secondary Mitochondrial Abnormalities

Child Neurology Open ◽

10.1177/2329048x19829520 ◽

2019 ◽

Vol 6 ◽

pp. 2329048X1982952 ◽

Cited By ~ 2

Author(s):

Aneal Khan ◽

Jennifer Bennett ◽

Morris H. Scantlebury ◽

Xing-Chang Wei ◽

Marina Kerr

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Stop Codon ◽

Premature Stop Codon ◽

Monozygotic Twins ◽

Trna Synthetase ◽

Resonance Spectroscopy ◽

Multifunctional Protein ◽

Whole Exome ◽

Long Term Follow Up

Aminoacyl transfer RNA (tRNA) synthetase complex-interacting multifunctional protein I is a noncatalytic component of tRNA multi-synthetase complexes. Although important in joining tRNAs to their cognate amino acids, AIMP1 has several other functions including axonal growth, cytokine activity, and interactions with N-acetylaspartic acid in ribosomal tRNA synthetase complexes. Further, N-acetylaspartic acid donates an aspartate during myelination and is therefore important to axonal integrity. Mutations in AIMP1 can disrupt these functions, as demonstrated in this clinical case study of 2 monozygotic twins, who display congenital opisthotonus, microcephaly, severe developmental delay, and seizures. Whole exome sequencing was used to identify a premature stop codon in the AIMP1 gene (g. 107248613_c.115C>T; p.(Gln39). In the absence of whole exome sequencing, we propose that decreased N-acetylaspartic acid peaks on magnetic resonance spectroscopy could act as a biomarker for AIMP1 mutations.

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Whole exome sequencing identifies compound heterozygous variants of CR2 gene in monozygotic twin patients with common variable immunodeficiency

SAGE Open Medicine ◽

10.1177/2050312120922652 ◽

2020 ◽

Vol 8 ◽

pp. 205031212092265

Author(s):

Adiratna Mat Ripen ◽

Hamidah Ghani ◽

Chai Teng Chear ◽

Mei Yee Chiow ◽

Sharifah Nurul Husna Syed Yahya ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Complex Disease ◽

Monozygotic Twins ◽

Compound Heterozygous ◽

Sequencing Analysis ◽

Missense Mutations ◽

Upper Respiratory Tract ◽

Whole Exome ◽

Tract Infections

Objectives: A pair of female Malay monozygotic twins who presented with recurrent upper respiratory tract infections, hepatosplenomegaly, bronchiectasis and bicytopenia were recruited in this study. Both patients were suspected with primary immunodeficiency diseases. However, the definite diagnosis was not clear due to complex disease phenotypes. The objective of this study was to identify the causative gene mutation in these patients. Methods: Lymphocyte subset enumeration test and whole exome sequencing were performed. Results: We identified a compound heterozygous CR2 mutation (c.1916G>A and c.2012G>A) in both patients. These variants were then confirmed using Sanger sequencing. Conclusion: Whole exome sequencing analysis of the monozygotic twins revealed compound heterozygous missense mutations in CR2.

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Whole-exome sequencing for monozygotic twins discordant for hemifacial microsomia

Journal of Cranio-Maxillofacial Surgery ◽

10.1016/j.jcms.2018.02.005 ◽

2018 ◽

Vol 46 (5) ◽

pp. 802-807 ◽

Cited By ~ 3

Author(s):

Xiaojun Chen ◽

Feng Xu ◽

Fatao Liu ◽

Zin Mar Aung ◽

Wei Chen ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Monozygotic Twins ◽

Hemifacial Microsomia ◽

Whole Exome

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DMC1 mutation that causes human non-obstructive azoospermia and premature ovarian insufficiency identified by whole-exome sequencing

Journal of Medical Genetics ◽

10.1136/jmedgenet-2017-104992 ◽

2018 ◽

Vol 55 (3) ◽

pp. 198-204 ◽

Cited By ~ 24

Author(s):

Wen-Bin He ◽

Chao-Feng Tu ◽

Qiang Liu ◽

Lan-Lan Meng ◽

Shi-Min Yuan ◽

...

Keyword(s):

Exome Sequencing ◽

Missense Mutation ◽

Whole Exome Sequencing ◽

Male Patient ◽

Histological Analysis ◽

Pedigree Analysis ◽

Obstructive Azoospermia ◽

Ovarian Insufficiency ◽

Causative Gene ◽

Whole Exome

BackgroundThe genetic causes of the majority of male and female infertility caused by human non-obstructive azoospermia (NOA) and premature ovarian insufficiency (POI) with meiotic arrest are unknown.ObjectiveTo identify the genetic cause of NOA and POI in two affected members from a consanguineous Chinese family.MethodsWe performed whole-exome sequencing of DNA from both affected patients. The identified candidate causative gene was further verified by Sanger sequencing for pedigree analysis in this family. In silico analysis was performed to functionally characterise the mutation, and histological analysis was performed using the biopsied testicle sample from the male patient with NOA.ResultsWe identified a novel homozygous missense mutation (NM_007068.3: c.106G>A, p.Asp36Asn) in DMC1, which cosegregated with NOA and POI phenotypes in this family. The identified missense mutation resulted in the substitution of a conserved aspartic residue with asparaginate in the modified H3TH motif of DMC1. This substitution results in protein misfolding. Histological analysis demonstrated a lack of spermatozoa in the male patient’s seminiferous tubules. Immunohistochemistry using a testis biopsy sample from the male patient showed that spermatogenesis was blocked at the zygotene stage during meiotic prophase I.ConclusionsTo the best of our knowledge, this is the first report identifying DMC1 as the causative gene for human NOA and POI. Furthermore, our pedigree analysis shows an autosomal recessive mode of inheritance for NOA and POI caused by DMC1 in this family.

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