Identification of copy number variants in miscarriages from couples with idiopathic recurrent pregnancy loss

Abstract BACKGROUND Approximately 50% of pregnancy losses are caused by chromosomal abnormalities, such as aneuploidy. The remainder has an apparent euploid karyotype, but it is plausible that there are cases of pregnancy loss with other genetic aberrations that are not currently routinely detected. Studies investigating the use of exome sequencing and chromosomal microarrays in structurally abnormal pregnancies and developmental disorders have demonstrated their clinical application and/or potential utility in these groups of patients. Similarly, there have been several studies that have sought to identify genes that are potentially causative of, or associated with, spontaneous pregnancy loss, but the evidence has not yet been synthesized. OBJECTIVE AND RATIONALE The objective was to identify studies that have recorded monogenic genetic contributions to pregnancy loss in euploid pregnancies, establish evidence for genetic causes of pregnancy loss, identify the limitations of current evidence, and make recommendations for future studies. This evidence is important in considering additional research into Mendelian causes of pregnancy loss and appropriate genetic investigations for couples experiencing recurrent pregnancy loss. SEARCH METHODS A systematic review was conducted in MEDLINE (1946 to May 2018) and Embase (1974 to May 2018). The search terms ‘spontaneous abortion’, ‘miscarriage’, ‘pregnancy loss’, or ‘lethal’ were used to identify pregnancy loss terms. These were combined with search terms to identify the genetic contribution including ‘exome’, ‘human genome’, ‘sequencing analysis’, ‘sequencing’, ‘copy number variation’, ‘single-nucleotide polymorphism’, ‘microarray analysis’, and ‘comparative genomic hybridization’. Studies were limited to pregnancy loss up to 20 weeks in humans and excluded if the genetic content included genes that are not lethal in utero, PGD studies, infertility studies, expression studies, aneuploidy with no recurrence risk, methodologies where there is no clinical relevance, and complex genetic studies. The quality of the studies was assessed using a modified version of the Newcastle–Ottawa scale. OUTCOMES A total of 50 studies were identified and categorized into three themes: whole-exome sequencing studies; copy number variation studies; and other studies related to pregnancy loss including recurrent molar pregnancies, epigenetics, and mitochondrial DNA aberrations. Putatively causative variants were found in a range of genes, including CHRNA1 (cholinergic receptor, nicotinic, alpha polypeptide 1), DYNC2H1 (dynein, cytoplasmic 2, heavy chain 1), and RYR1 (ryanodine receptor 1), which were identified in multiple studies. Copy number variants were also identified to have a causal or associated link with recurrent miscarriage. WIDER IMPLICATIONS Identification of genes that are causative of or predisposing to pregnancy loss will be of significant individual patient impact with respect to counselling and treatment. In addition, knowledge of specific genes that contribute to pregnancy loss could also be of importance in designing a diagnostic sequencing panel for patients with recurrent pregnancy loss and also in understanding the biological pathways that can cause pregnancy loss.

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Copy number variation profile in the placental and parental genomes of recurrent pregnancy loss families

Scientific Reports ◽

10.1038/srep45327 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 10

Author(s):

Laura Kasak ◽

Kristiina Rull ◽

Siim Sõber ◽

Maris Laan

Keyword(s):

Copy Number Variation ◽

Copy Number ◽

Pregnancy Loss ◽

Recurrent Pregnancy Loss ◽

Number Variation

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P–381 Deciphering the genetic cause of recurrent and sporadic pregnancy loss

Human Reproduction ◽

10.1093/humrep/deab130.380 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

R Essers ◽

G Acharya ◽

S Al-Nasiry ◽

H Brunner ◽

S P Deligiannis ◽

...

Keyword(s):

Copy Number ◽

Pregnancy Loss ◽

Recurrent Pregnancy Loss ◽

De Novo ◽

Snp Array ◽

Paternal Age ◽

Chromosome 5 ◽

Chorionic Villi ◽

Genome Wide ◽

Extraembryonic Mesoderm

Abstract Study question To investigate the prevalence and effect of (mosaic) de novo genomic aberrations in recurrent pregnancy loss (RPL) and sporadic abortion (SA). Summary answer Prevalence of maternal uniparental disomies (UPDs) was high in both cohorts. While chromosomal UPDs were found in both cohorts, genome wide UPDs were RPL specific. What is known already Spontaneous abortion occurs in 10–15% of clinically recognized pregnancies and recurrent pregnancy loss in 1–3%. SA and RPL are associated with reduced quality of life. Multiple factors contribute to SA and RPL, such as uterine malformations and parental/fetal chromosomal abnormalities. However, in ∼60% of SA and RPL the cause remains unknown. UPD is defined as the presence of two homologues chromosomes originating from a single parent. This phenomenon can lead to imprinting disorders that are characterised by clinical features affecting growth, development and metabolism in liveborn offspring. However, it could also be responsible for pregnancy loss. Study design, size, duration We recruited 32 families with pregnancy loss (n = 16 RPL cohort, n = 16 SA cohort) with no known genetic predispositions and normal karyotyping results in both parents and the fetus. Average maternal age was 28.68 years (SD = 5.43), paternal age 30.3 years (SD = 5.53), and the gestational age at pregnancy loss was 8.65 weeks (SD = 2.47). The average number of miscarriages in the RPL group was 3.57 (SD = 0.84). We profiled the genomic landscape of both cohorts using SNP typing. Participants/materials, setting, methods We isolated DNA from blood of both parents and the placental tissues from the miscarried products of conception. The placenta tissues were sampled from two distinct extraembryonic and embryonic germ layers, the extraembryonic mesoderm and the chorionic villi cytotrophoblast. Subsequently, we performed SNP-genotyping using Illumina’s Global-Screening Array–24 v2.0 BeadChips and applied haplarithmisis to delineate allelic architecture of fetal tissues of both cohorts. This allowed us to detect large de novo copy-number and -neutral (>10kb) changes. Main results and the role of chance In this pilot study, we have analyzed 132 DNA samples (n = 32 families), of which 16 families were in the RPL cohort and 16 in the SA cohort. Within the RPL cohort, we found: one family with mosaic genome wide hexaploidy both in the extraembryonic mesoderm and chorionic villi, one family with a non-mosaic genome wide hetero UPD of the chorionic villi tissue, one family with a mosaic UPD of chromosome 14 in both tissues and tetraploidy exclusively in the chorionic villi, one family with a mosaic UPD of chromosome 16 in both tissues, one family with a mosaic UPD of chromosome 6 in both tissues, and another family with a mosaic UPD of chromosome 5 in the extraembryonic mesoderm. Within the SA group, one family showed a UPD of chromosome 7 and another family showed a segmental UPD of chromosome 5 in both tissues. Strikingly, all the UPDs found in this study were maternal in origin. Limitations, reasons for caution The main limitation of this study is the resolution of detecting copy-neutral and copy-number variations, which is an inherent limiting factor of SNP-array technology. In addition, in the sample in which we observed non-mosaic genome wide UPD, maternal contamination is likely that can be investigated by other technologies. Wider implications of the findings: Multiple genome wide UPDs are found in the RPL group but none in the SA group, indicating an association between genome wide mosaic UPD and RPL. These findings could lead to a better understanding of causative factors for SA and RPL and the need for a SNP-based non-invasive prenatal testing. Trial registration number Not applicable

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Role of DNA copy number variations in genetic predisposition to recurrent pregnancy loss

Journal of Reproductive Immunology ◽

10.1016/j.jri.2011.06.028 ◽

2011 ◽

Vol 90 (2) ◽

pp. 145 ◽

Cited By ~ 2

Author(s):

L. Nagirnaja ◽

L. Kasak ◽

P. Palta ◽

K. Rull ◽

O.B. Christiansen ◽

...

Keyword(s):

Genetic Predisposition ◽

Copy Number ◽

Pregnancy Loss ◽

Recurrent Pregnancy Loss ◽

Copy Number Variations ◽

Dna Copy Number ◽

Dna Copy Number Variations

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Understanding Schizophrenia: Genetic Causes and Treatment

Current Neuropsychiatry and Clinical Neuroscience Reports ◽

10.33702/cncnr.2019.1.1.2 ◽

2019 ◽

Vol 1 (1) ◽

pp. 6-12

Author(s):

Fatima Javeria ◽

Shazma Altaf ◽

Alishah Zair ◽

Rana Khalid Iqbal

Keyword(s):

Copy Number ◽

Drug Targets ◽

Disease Risk ◽

Mental Disease ◽

Copy Number Variants ◽

Aminobutyric Acid ◽

Epigenetic Mechanisms ◽

Gamma Aminobutyric Acid ◽

Wide Range ◽

Severe Mental Disease

Schizophrenia is a severe mental disease. The word schizophrenia literally means split mind. There are three major categories of symptoms which include positive, negative and cognitive symptoms. The disease is characterized by symptoms of hallucination, delusions, disorganized thinking and speech. Schizophrenia is related to many other mental and psychological problems like suicide, depression, hallucinations. Including these, it is also a problem for the patient’s family and the caregiver. There is no clear reason for the disease, but with the advances in molecular genetics; certain epigenetic mechanisms are involved in the pathophysiology of the disease. Epigenetic mechanisms that are mainly involved are the DNA methylation, copy number variants. With the advent of GWAS, a wide range of SNPs is found linked with the etiology of schizophrenia. These SNPs serve as ‘hubs’; because these all are integrating with each other in causing of schizophrenia risk. Until recently, there is no treatment available to cure the disease; but anti-psychotics can reduce the disease risk by minimizing its symptoms. Dopamine, serotonin, gamma-aminobutyric acid, are the neurotransmitters which serve as drug targets in the treatment of schizophrenia. Due to the involvement of genetic and epigenetic mechanisms, drugs available are already targeting certain genes involved in the etiology of the disease.

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