Customer Publications; Spotlight on Congenital Defects and Early Development

         March 31, 2020

In these very uncertain times, it has been uplifting to read the wonderful work Golden Helix customers have been doing across the globe! This month, the focus of this blog is on published articles relating to congenital defects and early development. Congratulations to all our customers who have published papers and please enjoy a small sampling of their work. To access the link to their full articles, just click on the title of each one. Enjoy and stay safe!

Association of Estrogen Receptor Gene Variants (ESR1 and ESR2) with Polycystic Ovary Syndrome in Tunisia

Polycystic Ovary Syndrome (PCOS) is a complex disease affecting women at reproductive age, characterized by anovulation, hyperandrogenism and polycystic ovaries. The condition may also be characterized by obesity, dyslipidemia and intrinsic insulin resistance, putting women affected by PCOS at greater risk for developing type 2 diabetes and metabolic syndrome (MetS). Building on studies previously done in different ethnic populations, researchers from France and Tunisia teamed up to investigate the role single nucleotide variations (SNV) in the ESR1 & ESR2 genes play in PCOS in a population of Tunisian women. Using SVS software for their statistical analysis for genetic association as well as haplotype association, the team used the results of their study to provide evidence of genetic association of widely used SNV’s in both genes with PCOS in this Tunisian population, suggesting they are good markers for PCOS in this region of the world.

Florin Grigorescu & Colleagues, University of Montpellier / Published in Gene 

Genome Sequencing of Human In Vitro Fertilisation Embryos for Pathogenic Variation Screening

Australian researchers performed a pilot study to test the value of whole genome sequencing (WGS) intended to aid in embryo selection in high-risk couples engaged in in vitro fertilization (IVF) treatment. Although a controversial topic, the team intends to take advantage of recent advancements in next generation sequencing to assist with selecting embryos for implantation to prevent early life fatal genetic conditions which adversely affect the quality of life of the afflicted individuals and their families. Using a small number of IVF couples and their IVF embryos, the team obtained trophectoderm cell biopsy samples from the embryos and genomic DNA from the blood of the parents to detect inherited pathogenic and high-risk de novo variations in a first of its kind study design. With the help of VarSeq software for the single nucleotide polymorphism (SNP) and indel analysis, they classified the variants according to ACMG standards and guidelines. They also used VarSeq in their trio analysis of copy number variations and structural variations. The results of this pilot study supported further investigation of using WGS in IVF to screen embryos intended for implantation for pathogenic, severe disease-causing and high risk de novo mutations that can be passed from parents to offspring. It is also possible this method could aid in the diagnosis of the root cause of a couple’s subfertility providing valuable information aimed at producing a viable pregnancy.

Nicholas Murphy & Colleagues, Monash IVF / Published in Nature Scientific Reports

Whole Exome Sequencing Identifies Multiple Novel Candidate Genes in Familial Gastroschisis

Gastroschisis is a rare defect apparent at birth in which the intestines protrude through the right side of the umbilical ring while an intact umbilical cord is present on the left. This condition, although rare, is seen with increasing prevalence and the etiology is poorly understood. With no known attempts to investigate the heritable factors using next generation sequencing (NGS) and whole exome sequencing (WES), a research team from Mexico endeavored to better understand the genetic basis of the defect in a family with a recurrence of gastroschisis. SVS was used to filter and prioritize candidate genes in their WES analysis, which was based on the Human Genome annotation, GRCh37/hg19. The results of their study suggested a complex interplay between genetic and environmental factors could share a role in the development of gastroschisis. It is possible this initial study will pave the way for more studies of its kind to further understand the underlying factors causing gastroschisis.

Hugo Gallardo-Blanco & Colleagues, The Autonomous University of Nuevo Leon / Published in Molecular Genetics & Genomic Medicine

NKX2-6 Related Congenital Heart Disease: Biallelic Homeodomain-disrupting Variants and Truncus Arteriosus

Investigators from across the US teamed up to study a rare congenital heart defect (CHD) called truncus arteriosus (TA). TA is a condition where a single blood vessel comes out of the right and left ventricles, instead of the pulmonary artery and aorta in normal conditions. The cause of this condition is unknown in most cases. Babies with TA will have severe circulatory problems and will present with symptoms in the first few days after birth. In this study, two children from a non-consanguineous family were found to have the same compound heterozygous variants that were identified as the likely cause of the defect. With the help of SVS software, biallelic variants were found in the NKX2-6 gene, which led the team to surmise that the unique nature of the mutations may disrupt the normal gene function, resulting in the presented phenotypes. The team hopes these findings will result in additional studies of NKX2-6 variations in patients and families with conotruncal defects thus further defining the role they play in these rare congenital heart conditions.

Petra Werner & Colleagues, Children’s Hospital of Philadelphia / Published in the American Journal of Medical Genetics

Common Variants in the COL2A1 Gene are Associated with Lattice Degeneration of the Retina in a Japanese Population

Researchers from Japan recently engaged in a pilot study to investigate the role of collagen type II alpha 1 (COL2A1) gene variants in the development of disorders associated with retinal detachment. Focusing on a condition called lattice degeneration of the retina, the team used SVS software for the association analysis, stepwise regression analysis and linkage disequilibrium estimation on a study population of 643 affected patients and 1,694 healthy control subjects. They were able to demonstrate that the COL2A1 intronic SNP rs1793954 had a significant impact on disease development. Their findings suggest the possibility that rs1793954 contributes to an altered COL2A1 expression which may be involved in the development of lattice degeneration of the retina. The team hopes their results will open the door to further genetic and functional analysis of COL2A1 variants to validate its role in this inherited, congenital abnormality of the retina.

Akira Meguro & Colleagues, Yokohama City University Graduate School of Medicine / Published in Molecular Vision

The Interaction Between Cannabis Use and a CB1-related Polygenic Co-expression Index Modulates Dorsolateral Prefrontal Activity During Working Memory Processing

Building on previously published studies, a team of investigators from Italy designed a study to investigate if co-expression of a molecular network including the cannabinoid CB1 receptor coding gene (CNR1) interacts with cannabis use in modulating working memory processing in human subjects. The team combined methods using postmortem prefrontal data and an in vivo component using imaging and behavioral methods to assess working memory in young adults. SVS software was used to perform a gene set-wide association study of SNP data to map the gene set onto a genomic reference in order to translate postmortem findings into the living brain. They created a polygenic score, combining the effects of SNPs on co-expression of the cohesive gene set which included CNR1. They then computed the score in the in vivo portion of the study to observe the interactions of cannabis use on brain activity during working memory. Their newly designed approach may function as a useful model for studying the interactions of complex genetic systems and cannabis use.  The team also hopes this design will increase knowledge of the mechanisms of interactions between genetic features and environmental variables hidden within other cognitive phenotypes.

Alessandro Bertolino & Colleagues, University of Bari / Published in Brain Imaging and Behavior

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