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News Article | February 24, 2017
Site: www.eurekalert.org

The genetic material of an organism encodes the instructions that guide its development. These codes are not written in stone; they can change or mutate any time during the life of the organism. Single changes in the code can occur spontaneously, as a mutation, causing developmental problems. Others, as an international team of researchers has discovered, are too numerous to be explained by random mutation processes present in the general population. When such multiple genetic changes occur before or early after conception, they may inform scientists about fundamental knowledge underlying many diseases. The study appears in Cell. "As a part of the clinical evaluation of young patients with a variety of developmental issues, we performed clinical genomic studies and analyzed the genetic material of more than 60,000 individuals. Most of the samples were analyzed at Baylor Genetics laboratories," said lead author Dr. Pengfei Liu, assistant professor of molecular and human genetics Baylor College of Medicine and assistant laboratory director of Baylor Genetics. "Of these samples, five had extreme numbers of genetic changes that could not be explained by random events alone." The researchers looked at a type of genetic change called copy number variants, which refers to the number of copies of genes in human DNA. Normally we each have two copies of each gene located on a pair of homologous chromosomes. "Copy number variants in human DNA can be compared to repeated or missing paragraphs or pages of text in a book," said senior author Dr. James R. Lupski, Cullen Professor of Molecular and Human Genetics at Baylor. "For instance, if one or two pages are duplicated in a book it could be explained by random mistakes. On the other hand, if 10 different pages are duplicated, you have to suspect that it did not happen by chance. We want to understand the basic mechanism underlying these multiple new copy number variant mutations in the human genome." A rare, early and transitory phenomenon that can affect human development The researchers call this phenomenon multiple de novo copy number variants. As the name indicates, the copy number variants are many and new (de novo). The latter means that the patients carrying the genetic changes did not inherit them from their parents because neither the mother nor the father carries the changes. In this rare phenomenon, the copy number variants are predominantly gains - duplications and triplications - rather than losses of genetic material, and are present in all the cells of the child. The last piece of evidence together with the fact that the parents do not carry the alterations suggest that the extra copies of genes may have occurred either in the sperm or the egg, the parent's germ cells, and before or very early after fertilization. "This burst of genetic changes happens only during the early stages of embryonic development and then it stops," Liu said. "Interestingly, despite having a large number of mutations, the young patients present with relatively mild neurological problems." The researchers are analyzing more patient samples looking for additional cases of multiple copy number variants to continue their investigation of what may trigger this rare phenomenon. "We hope that as more researchers around the world learn about this and confirm it, the number of cases will increase," Liu said. "This will improve our understanding of the underlying mechanism and of why and how pathogenic copy number variants arise not only in developmental disorders but in cancers." "A new era of clinical genomics-supported medicine and research" This discovery has been possible in great measure thanks to the breadth of genetic testing performed and genomic data available at Baylor Genetics laboratory. "The diagnostics lab Baylor Genetics is one of the pioneers in this new era of clinical genomics-supported medical practice and disease gene discovery research," Lupski said. "They are developing the clinical genomics necessary to foster and support the Precision Medicine Initiative of the National Institutes of Health, and generating the genomics data that further drives human genome research." Using state-of-the art technologies and highly-trained personnel, Baylor Genetics analyzes hundreds of samples daily for genetic evaluation of patients with conditions suspected to have underlying genetic factors potentially contributing to their disease. Having this wealth of information and insight into the genetic mechanisms of disease offers now the possibility of advancing medicine and basic research in ways that were not available before. "There is so much that both clinicians and researchers can learn from the data generated in diagnostic labs," Liu said. "Clinicians receive genomic information that can aid in diagnosis and treatment of their patients, and researchers gather data that can help them unveil the mechanisms underlying the biological perturbations resulting in the patients' conditions." Other contributors to this work include Bo Yuan, Claudia M.B. Carvalho, Arthur Wuster, Klaudia Walter, Ling Zhang, Tomasz Gambin, Zechen Chong, Ian M. Campbell, Zeynep Coban Akdemir, Violet Gelowani, Karin Writzl, Carlos A. Bacino, Sarah J. Lindsay, Marjorie Withers, Claudia Gonzaga-Jauregui, Joanna Wiszniewska, Jennifer Scull, Pawel Stankiewicz, Shalini N. Jhangiani, Donna M. Muzny, Feng Zhang, Ken Chen, Richard A. Gibbs, Bernd Rautenstrauss, Sau Wai Cheung, Janice Smith, Amy Breman, Chad A. Shaw, Ankita Patel and Matthew E. Hurles. The researchers are affiliated with one of more of the following institutions Baylor, Wellcome Trust Sanger Institute in the U.K., Fudan University in China, the University of Texas MD Anderson Cancer Center Houston, the Clinical Institute of Medical Genetics in Slovenia and the Medical Genetics Center in Germany. This work was supported in part by grants from the US National Institute of Neurological Disorders and Stroke (R01NS058529), the National Human Genome Research Institute (U54HG003273), a joint NHGRI/National Heart Blood and Lung Institute grant (U54HG006542) to the Baylor Hopkins Center for Mendelian Genomics, and the BCM Intellectual and Developmental Disabilities Research Center, IDDRC Grant Number 5P30HD024064-23, from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The work was also partially supported by the Wellcome Trust (WT098051).


Pereza N.,University of Rijeka | Peterlin B.,Clinical Institute of Medical Genetics | Volk M.,Clinical Institute of Medical Genetics | Kapovic M.,University of Rijeka | Ostojic S.,University of Rijeka
Molecular Human Reproduction | Year: 2014

A number of case-control studies investigated the association between idiopathic recurrent spontaneous abortion (IRSA) and variations in the gene encoding endothelial nitric oxide synthase (NOS3), but yielded contradictory results. Our aim was to test the association of the NOS3 variable number of tandem repeats (VNTR) in intron 4 and +894 G/T single-nucleotide polymorphism (SNP) with IRSA in Slovenian women(148 IRSA and 149 control women), conduct a systematic review of literature on the association betweenNOS3gene variations and IRSA, and perform meta-analyses of studies that met the inclusion criteria, defined by virtue of the European Society for Human Reproduction and Embryology evidence-based guidelines for recurrent spontaneous abortion. Genotyping was performed using PCR and restriction fragment length polymorphism methods. The systematic review of literature (English language) was conducted using PubMed and Scopus databases, to 1 November 2014.We determined no association of IRSA with the VNTR in intron 4 and +894 G/T SNP in Slovenian women. Furthermore, 16 case-control studies were identified on the association between 15 NOS3 gene variations and IRSA. However, significant inconsistencies exist in the selection criteria of patients and controls between studies. The meta-analysis of VNTR in intron 4 was performed on five studies (894 patients, 944 controls), whereas the meta-analysis of +894 G/T SNP included six studies (1111 patients, 1121 controls). The association with IRSAwas significant for the+894G/TSNP under thedominant geneticmodel (GT+TTversusGG) based on fixed (odds ratio (OR) 1/4 1.54, 95% confidence interval (CI) 1/4 1.28-1.86, P 1/4 ,0.01) and randomeffects models (OR 1/4 1.54, 95% CI 1/4 1.03-2.31, P 1/4 0.03). In conclusion, the GTand TT genotypes of the +894 G/T SNP in women might contribute to a predisposition to IRSA. Additional genetic association and functional studies in different populations with larger numbers of participants and a uniformly defined IRSA are needed to clarify the contribution of NOS3 +894 G/T gene variation to IRSA. © The Author 2015.


Pereza N.,University of Rijeka | Ostojic S.,University of Rijeka | Smircic A.,University of Rijeka | Hodzic A.,Clinical Institute of Medical Genetics | And 2 more authors.
Journal of Assisted Reproduction and Genetics | Year: 2015

Purpose: The vascular endothelial growth factor A (VEGFA) is crucial for normal vasculogenesis and angiogenesis during pregnancy, and alterations in the VEGFA gene expression were detected in women with idiopathic recurrent spontaneous abortion (IRSA) and spontaneously aborted conceptuses. Our aim was to evaluate whether there is an association between the functional −2549 insertion/deletion (I/D) polymorphism in the promoter region of the VEGFA gene and IRSA in reproductive couples. Methods: We performed a case-control study involving 149 women and their 140 partners with three or more IRSA and 149 control women and men. Allele-specific polymerase chain reaction was used for genotyping. Results: We found no association of the −2549 I/D polymorphism with IRSA in women. However, men with the DD genotype have a 1.75-fold increased risk of IRSA compared with men carrying the ID and II genotypes (95 % confidence interval (CI) = 1.05–2.93, P = 0.032). In addition, the D allele in men contributes to a 1.42-fold increased risk of IRSA (95 % CI = 1.02–1.97, P = 0.036) compared to men carrying the I allele. Conclusions: Our results indicate that the −2549 I/D polymorphism in the VEGFA gene in men might be associated with IRSA. Additional genetic association studies including both partners, as well as expression studies, are needed to elucidate the role of this polymorphism in IRSA. © 2015, Springer Science+Business Media New York.


PubMed | University of Rijeka and Clinical Institute of Medical Genetics
Type: | Journal: Journal of assisted reproduction and genetics | Year: 2016

The aim of this study was to investigate the potential association of matrix metalloproteinase 7 (MMP7) -181 A/G and MMP12 -82 A/G functional single nucleotide polymorphisms (SNP) with idiopathic recurrent spontaneous abortion (IRSA) in Slovenian reproductive couples.A case-control study was conducted on 149 couples with 3 or more consecutive idiopathic spontaneous pregnancy loses and 149 women and men with at least 2 live births and no history of pregnancy complications. Genotyping of MMP7 -181 A/G and MMP12 -82 A/G SNPs was performed using polymerase chain reaction and restriction fragment length polymorphism methods.There were no statistically significant differences in the distribution of MMP7 -181 A/G and MMP12 -82 A/G genotype, allele, or haplotype frequencies between IRSA patients and controls, as well as patients primary and secondary IRSA. We also found no association of MMP7 -181 A/G and MMP12 -82 A/G genotypes, alleles, and haplotypes with IRSA.We found no evidence to support the association between IRSA and MMP7 -181 A/G and MMP12 -82 A/G SNPs in Slovenian reproductive couples.


PubMed | University of Rijeka and Clinical Institute of Medical Genetics
Type: Journal Article | Journal: Journal of assisted reproduction and genetics | Year: 2016

The vascular endothelial growth factor A (VEGFA) is crucial for normal vasculogenesis and angiogenesis during pregnancy, and alterations in the VEGFA gene expression were detected in women with idiopathic recurrent spontaneous abortion (IRSA) and spontaneously aborted conceptuses. Our aim was to evaluate whether there is an association between the functional -2549 insertion/deletion (I/D) polymorphism in the promoter region of the VEGFA gene and IRSA in reproductive couples.We performed a case-control study involving 149 women and their 140 partners with three or more IRSA and 149 control women and men. Allele-specific polymerase chain reaction was used for genotyping.We found no association of the -2549 I/D polymorphism with IRSA in women. However, men with the DD genotype have a 1.75-fold increased risk of IRSA compared with men carrying the ID and II genotypes (95 % confidence interval (CI)=1.05-2.93, P=0.032). In addition, the D allele in men contributes to a 1.42-fold increased risk of IRSA (95 % CI=1.02-1.97, P=0.036) compared to men carrying the I allele.Our results indicate that the -2549 I/D polymorphism in the VEGFA gene in men might be associated with IRSA. Additional genetic association studies including both partners, as well as expression studies, are needed to elucidate the role of this polymorphism in IRSA.


PubMed | University of Rijeka and Clinical Institute of Medical Genetics
Type: Journal Article | Journal: Molecular human reproduction | Year: 2015

A number of case-control studies investigated the association between idiopathic recurrent spontaneous abortion (IRSA) and variations in the gene encoding endothelial nitric oxide synthase (NOS3), but yielded contradictory results. Our aim was to test the association of the NOS3 variable number of tandem repeats (VNTR) in intron 4 and +894 G/T single-nucleotide polymorphism (SNP) with IRSA in Slovenian women (148 IRSA and 149 control women), conduct a systematic review of literature on the association between NOS3 gene variations and IRSA, and perform meta-analyses of studies that met the inclusion criteria, defined by virtue of the European Society for Human Reproduction and Embryology evidence-based guidelines for recurrent spontaneous abortion. Genotyping was performed using PCR and restriction fragment length polymorphism methods. The systematic review of literature (English language) was conducted using PubMed and Scopus databases, to 1 November 2014. We determined no association of IRSA with the VNTR in intron 4 and +894 G/T SNP in Slovenian women. Furthermore, 16 case-control studies were identified on the association between 15 NOS3 gene variations and IRSA. However, significant inconsistencies exist in the selection criteria of patients and controls between studies. The meta-analysis of VNTR in intron 4 was performed on five studies (894 patients, 944 controls), whereas the meta-analysis of +894 G/T SNP included six studies (1111 patients, 1121 controls). The association with IRSA was significant for the +894 G/T SNP under the dominant genetic model (GT+TT versus GG) based on fixed (odds ratio (OR) = 1.54, 95% confidence interval (CI) = 1.28-1.86, P = <0.01) and random effects models (OR = 1.54, 95% CI = 1.03-2.31, P = 0.03). In conclusion, the GT and TT genotypes of the +894 G/T SNP in women might contribute to a predisposition to IRSA. Additional genetic association and functional studies in different populations with larger numbers of participants and a uniformly defined IRSA are needed to clarify the contribution of NOS3 +894 G/T gene variation to IRSA.


Volk M.,Clinical Institute of Medical Genetics | Teran N.,Clinical Institute of Medical Genetics | Maver A.,Clinical Institute of Medical Genetics | Lovrecic L.,Clinical Institute of Medical Genetics | Peterlin B.,Clinical Institute of Medical Genetics
Paediatria Croatica | Year: 2015

Prenatal genetic testing is under the remit of the National Health Service in Slovenia and has been included in clinical routine since the 1980s. Traditionally, prenatal services have consisted of karyotyping and rapid fetal aneuploidy screening to detect chromosome abnormalities, whereas targeted mutation testing was used for single gene disorders. Development of array comparative genomic hybridization and next generation sequencing allows for genome analysis at better resolution in a single experiment. While technological advances in medicine continue to evolve, increasing diagnostic accuracy and broadening the spectrum of indications, all these innovations require more investment along with more equipment and higher staffing rations trained to use it, placing burden upon healthcare funding and expenditure. This prompts us to consider how to implement new techniques into the existing services in order to update genetic services for the 21st century. Our aim is to develop a new approach to prenatal genetic services, which would maximize diagnostic yield at an acceptable cost.

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