Customer Publications Throughout June 2021

         June 29, 2021

Golden Helix’s solutions are leveraged in a wide variety of scientific fields. As always, we are thrilled to showcase some of the newly published articles written by our customers. Here are a few that utilized VarSeq’s powerful scalability analyzing whole exome sequencing data. WES can identify variations in the protein-coding region of any gene. Since most known mutations that cause disease are found in the exons, WES seems to be a good method for identifying mutations that could potentially cause disease. The software’s capabilities are valuable, and you can read more about them here and here! I welcome you to read on and gain insight into how Golden Helix users are leading the advancement in understanding underlying genetic causes for disease by utilizing our powerful software.

MITO-FIND: A study in 390 patients to determine a diagnostic strategy for mitochondrial disease

A group of geneticists, doctors, and analysts from Pediatrics, Medical Genetics, Radiology, and Biochemistry & Molecular Biology at the University of Calgary collaborated to determine a diagnostic strategy for mitochondrial disease. These diseases have many clinical features involving many symptoms, including neurologic, muscular, cardiac, hepatic, visual, and auditory symptoms. As most patients prefer a non-invasive approach and the technical challenges associated with tissue biopsy, diagnosing mitochondrial disease proves challenging. NGS technology has made it easier to identify the clinically relevant variants that may lead to disease, and the researchers wanted to illustrate this. They evaluated the ability of their traditional diagnostic pathway (metabolite analysis, tissue neuropathology, and respiratory chain enzyme activity) in 390 patients. The traditional diagnostic pathway provided a diagnosis of mitochondrial disease in 115 patients (29.50%). Analysis of mtDNA, tissue neuropathology, skin electron microscopy, respiratory chain enzyme analysis using inhibitor assays, blue native polyacrylamide gel electrophoresis were all statistically significant in distinguishing patients between a mitochondrial and non-mitochondrial diagnosis. From these 390 patients who underwent traditional analysis, they recruited 116 patients for the NGS part of the study (36 patients who had a mitochondrial diagnosis (MITO) and 80 patients who had no diagnosis (No-Dx)). In the group of 36 MITO patients, nuclear whole exome sequencing (nWES) provided a second diagnosis in 2 cases who already had a pathogenic variant in mtDNA and a revised diagnosis (GLUL) in one case that had abnormal pathology but no pathogenic mtDNA variant. Their results showed that a non-invasive, bigenomic sequencing (BGS) approach (using both a nWES and optimized mtDNA analysis to include large deletions) should be the first step in investigating mitochondrial diseases. However, there may still be a role for tissue biopsy in unsolved cases or when the diagnosis is still unclear after NGS studies.

Kerr, M., Hume, S., Omar, F., Koo, D., Barnes, H., Khan, M., … Khan, A. (2020). MITO-FIND: A study in 390 patients to determine a diagnostic strategy for mitochondrial disease. Molecular Genetics and Metabolism. doi:10.1016/j.ymgme.2020.08.009 

Biallelic truncating variants in ATP9A cause a novel neurodevelopmental disorder involving postnatal microcephaly and failure to thrive

Dr. Felix Boschann, Institute of Medical Genetics and Human Genetics, at the Charité Universitätsmedizin Berlin and many other researchers from Germany and Austria set out to discover new disease genes related to intellectual disability. Genes implicated in the Golgi and endosomal trafficking machinery are crucial for brain development, and mutations in them are particularly associated with postnatal microcephaly (POM). The researchers performed exome sequencing in three affected individuals from two unrelated consanguineous families presenting with delayed neurodevelopment, intellectual disability of variable degree, POM, and failure to thrive. Patient-derived fibroblasts were tested for functional effects of the variants. They detected homozygous truncating variants in ATP9A. In addition, researchers identified two variants that lead to a substantial reduction of ATP9A mRNA expression. They also observed a strong overexpression of genes ARPC3 and SNX3, both of which strongly interacted with ATP9A. Their findings showed that pathogenic variants in ATP9A cause an autosomal recessive neurodevelopmental disorder with POM. While the physiological function of endogenous ATP9A is still largely elusive, their results underline a crucial role of this gene in endosomal transport in brain tissue.

Kerr, M., Hume, S., Omar, F., Koo, D., Barnes, H., Khan, M., … Khan, A. (2020). MITO-FIND: A study in 390 patients to determine a diagnostic strategy for mitochondrial disease. Molecular Genetics and Metabolism. doi:10.1016/j.ymgme.2020.08.009 

Biallelic variants in the endoplasmatic reticulum quality control mannosidase gene EDEM3 cause a congenital disorder of glycosylation comprising non-specific intellectual disability

A large group of researchers from the Netherlands, France, the UK, the United States, Portugal, and Canada collaborated on this recently published article. EDEM3 is involved in the endoplasmic reticulum-associated degradation pathway, responsible for recognizing misfolded proteins that the proteasome should ultimately degrade. In this study, researchers identified, through a combination of exome sequencing and gene matching, seven independent families with 11 individuals with bi-allelic protein-truncating variants and one individual with a compound heterozygous missense variant in EDEM3. The affected individuals present with an inherited congenital disorder of glycosylation (CDG) consisting of neurodevelopmental delay and variable facial dysmorphisms. Experiments in human fibroblast cell lines, human plasma, and mouse plasma and brain tissue demonstrated decreased trimming of Man8GlcNAc2 isomer B to Man7GlcNAc2, consistent with loss of EDEM3 enzymatic activity. In human cells, Man5GlcNAc2 to Man4GlcNAc2 conversion is also diminished with an increase of Glc1Man5GlcNAc2. Furthermore, analysis of the unfolded protein response showed a reduced increase in EIF2AK3 (PERK) expression upon stimulation with tunicamycin as compared to controls, suggesting an impaired unfolded protein response. The aberrant plasma N-glycan profile provides a quick, clinically available test for validating variants of uncertain significance that may be identified by molecular genetic testing. The researchers propose to call this deficiency EDEM3-CDG.

Polla, D., Edmondson, A., Duvet, S., March, M., Sousa, A., & Lehman, A. et al. (2021). Bi-allelic variants in the ER quality control mannosidase gene EDEM3 cause a congenital disorder of glycosylation. The American Journal Of Human Genetics. https://doi.org/10.1016/j.ajhg.2021.05.010

It is wonderful to read about our customers’ vital work, leveraging Golden Helix’s solutions. Please join us again next month, where we will showcase more of our customer’s published scientific articles. In the meantime, you can check out more blogs like this here.

About Dana Odenbeck

Dana Odenbeck is a sales and marketing associate at Golden Helix, joining the team in October of 2020. Dana graduated from Montana State University with a bachelor's degree in Ecology and Evolution. She strives to facilitate outbound prospecting and marketing initiatives alongside her gumptious team. Dana enjoys living and playing in the Greater Yellowstone ecosystem with her family, dogs, and friends.

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