Dataset Information

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

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.

SUBMITTER: Liu H

PROVIDER: S-EPMC7510158 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Liu Hongli H Wei Xiaoli X Sha Yanwei Y Liu Wensheng W Gao Haijie H Lin Jin J Li Youzhu Y Tang Yaling Y Wang Yifeng Y Wang Yanlong Y Su Zhiying Z

Journal of ovarian research 20200922 1

<h4>Background</h4>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.<h4>Methods</h4>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 pathogeni ...[more]

PMID: 32962729

Similar Datasets

Project description:BACKGROUND AND OBJECTIVES:Steroid-resistant nephrotic syndrome overwhelmingly progresses to ESRD. More than 30 monogenic genes have been identified to cause steroid-resistant nephrotic syndrome. We previously detected causative mutations using targeted panel sequencing in 30% of patients with steroid-resistant nephrotic syndrome. Panel sequencing has a number of limitations when compared with whole exome sequencing. We employed whole exome sequencing to detect monogenic causes of steroid-resistant nephrotic syndrome in an international cohort of 300 families. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:Three hundred thirty-five individuals with steroid-resistant nephrotic syndrome from 300 families were recruited from April of 1998 to June of 2016. Age of onset was restricted to <25 years of age. Exome data were evaluated for 33 known monogenic steroid-resistant nephrotic syndrome genes. RESULTS:In 74 of 300 families (25%), we identified a causative mutation in one of 20 genes known to cause steroid-resistant nephrotic syndrome. In 11 families (3.7%), we detected a mutation in a gene that causes a phenocopy of steroid-resistant nephrotic syndrome. This is consistent with our previously published identification of mutations using a panel approach. We detected a causative mutation in a known steroid-resistant nephrotic syndrome gene in 38% of consanguineous families and in 13% of nonconsanguineous families, and 48% of children with congenital nephrotic syndrome. A total of 68 different mutations were detected in 20 of 33 steroid-resistant nephrotic syndrome genes. Fifteen of these mutations were novel. NPHS1, PLCE1, NPHS2, and SMARCAL1 were the most common genes in which we detected a mutation. In another 28% of families, we detected mutations in one or more candidate genes for steroid-resistant nephrotic syndrome. CONCLUSIONS:Whole exome sequencing is a sensitive approach toward diagnosis of monogenic causes of steroid-resistant nephrotic syndrome. A molecular genetic diagnosis of steroid-resistant nephrotic syndrome may have important consequences for the management of treatment and kidney transplantation in steroid-resistant nephrotic syndrome.

Project description:BackgroundPremature ovarian insufficiency (POI) patients are predisposed to metabolic disturbances, including in lipid metabolism and glucose metabolism, and metabolic disorders appear to be a prerequisite of the typical long-term complications of POI, such as cardiovascular diseases or osteoporosis. However, the metabolic changes underlying the development of POI and its subsequent complications are incompletely understood, and there are few studies characterizing the disturbed metabolome in POI patients. The aim of this study was to characterize the plasma metabolome in POI by using ultrahigh-performance liquid chromatography-mass spectrometry (UHPLC-MS/MS) metabolomics and to evaluate whether these disturbances identified in the plasma metabolome relate to ovarian reserve and have diagnostic value in POI.MethodsThis observational study recruited 30 POI patients and 30 age- and body mass index (BMI)-matched controls in the Center for Reproductive Medicine, Department of Gynecology and Obstetrics, Nanfang Hospital, Southern Medical University, from January 2018 to October 2020. Fasting venous blood was collected at 9:00 am on days 2-4 of the menstrual cycle and centrifuged for analysis. An untargeted quantitative metabolomic analysis was performed using UHPLC-MS/MS.ResultsOur study identified 48 upregulated and 21 downregulated positive metabolites, and 13 upregulated and 48 downregulated negative metabolites in the plasma of POI patients. The differentially regulated metabolites were involved in pathways such as caffeine metabolism and ubiquinone and other terpenoid-quinone biosynthesis. Six metabolites with an AUC value > 0.8, including arachidonoyl amide, 3-hydroxy-3-methylbutanoic acid, dihexyl nonanedioate, 18-HETE, cystine, and PG (16:0/18:1), were correlated with ovarian reserve and thus have the potential to be diagnostic biomarkers of POI.ConclusionThis UHPLC-MS/MS untargeted metabolomics study revealed differentially expressed metabolites in the plasma of patients with POI. The differential metabolites may not only be involved in the aetiology of POI but also contribute to its major complications. These findings offer a panoramic view of the plasma metabolite changes caused by POI, which may provide useful diagnostic and therapeutic clues for POI disease.

Project description:Study hypothesisExome sequencing can identify genetic causes of idiopathic recurrent pregnancy loss (RPL).Study findingWe identified compound heterozygous deleterious mutations affecting DYNC2H1 and ALOX15 in two out of four families with RPL. Both genes have a role in early development. Bioinformatics analysis of all genes with rare and putatively pathogenic mutations in miscarriages and couples showed enrichment in pathways relevant to pregnancy loss, including the complement and coagulation cascades pathways.What is known alreadyNext generation sequencing (NGS) is increasingly being used to identify known and novel gene mutations in children with developmental delay and in fetuses with ultrasound-detected anomalies. In contrast, NGS is rarely used to study pregnancy loss. Chromosome microarray analysis detects putatively causative DNA copy number variants (CNVs) in ∼2% of miscarriages and CNVs of unknown significance (predominantly parental in origin) in up to 40% of miscarriages. Therefore, a large number of miscarriages still have an unknown cause.Study design, samples/materials, methodsWhole exome sequencing (WES) was performed using Illumina HiSeq 2000 platform on seven euploid miscarriages from four families with RPL. Golden Helix SVS v8.1.5 was used for data assessment and inheritance analysis for deleterious DNA variants predicted to severely disrupt protein-coding genes by introducing a frameshift, loss of the stop codon, gain of the stop codon, changes in splicing or the initial codon. Webgestalt (http://bioinfo.vanderbilt.edu/webgestalt/) was used for pathway and disease association enrichment analysis of a gene pool containing putatively pathogenic variants in miscarriages and couples in comparison to control gene pools.Main results and the role of chanceCompound heterozygous mutations in DYNC2H1 and ALOX15 were identified in miscarriages from two families with RPL. DYNC2H1 is involved in cilia biogenesis and has been associated with fetal lethality in humans. ALOX15 is expressed in placenta and its dysregulation has been associated with inflammation, placental, dysfunction, abnormal oxidative stress response and angiogenesis. The pool of putatively pathogenic single nucleotide variants (SNVs) and small insertions and deletions (indels) detected in the miscarriages showed enrichment in 'complement and coagulation cascades pathway', and 'ciliary motility disorders'. We conclude that CNVs, individual SNVs and pool of deleterious gene mutations identified by exome sequencing could contribute to RPL.Limitations, reasons for cautionThe size of our sample cohort is small. The functional effect of candidate mutations should be evaluated to determine whether the mutations are causative.Wider implications of the findingsThis is the first study to assess whether SNVs may contribute to the pathogenesis of miscarriage. Furthermore, our findings suggest that collective effect of mutations in relevant biological pathways could be implicated in RPL.Study funding and competing interestsThe study was funded by Canadian Institutes of Health Research (grant MOP 106467) and Michael Smith Foundation of Health Research Career Scholar salary award to ERS.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets