Customer Publications March 2022

         March 31, 2022

We at Golden Helix thoroughly enjoy seeing our software being utilized to solve problems and assist in the diagnosis of hereditary diseases. It is gratifying to be notified of customer publications in which they are doing precisely this. While there have been numerous publications this month showcasing Golden Helix software being applied, below are a few that stuck out specifically. The following all utilized our flagship software, VarSeq. VarSeq is a multi-tool for data analysis and allows for scalability, intuitive & repeatable workflows, and user friendliness. Our customers especially appreciate the ease of functionality and automated components for variant classification. So please continue reading to learn of a few examples of the VarSeq suite out in action and how it can help you with your data analysis!

Non-conventional Genetic Basis of Congenital Adrenal Hypoplasia in South Asia

Congenital adrenal hypoplasia or adrenal hypoplasia congenita (AHC) is a rare disorder ascribed to mutations in three genes, namely, the dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene 1 (DAX-1/NROB1 gene), steroidogenic factor-1 gene (SF-1/NR5A1 gene), and Achalasia-Addisonianism-Alacrima syndrome gene (AAAS gene). Five cases of AHC of local South Asian origin are described here. Golden Helix VarSeq 2.2.0 (Golden Helix Inc., Bozeman, MT, United States), the clinical genomics interpretation and reporting platform, was used for genetic study. No subject had congenital adrenal hyperplasia (CAH). Four male neonates presented with hypoglycemia, and one older female child presented with hyperpigmentation. This girl had a recognized mutation in the AAAS gene, while none of the four male neonates had any of the recognized mutations associated with AHC. Further, none were salt-losing, which is the conventional Western phenotype. Thus, additional, yet unknown, gene(s) must be operative in AHC among South Asian subsets.

Chatterjee S, Majumder A (March 26, 2022) Non-conventional Genetic Basis of Congenital Adrenal Hypoplasia in South Asia. Cureus 14(3): e23527. doi:10.7759/cureus.23527

Whole genome sequencing identifies rare genetic variants in familial pancreatic cancer patients

Pancreatic ductal adenocarcinoma (PDAC) represents one of the most lethal malignancies with very high mortality and short survival time. About 5–10% of the PDAC patients have a familial predisposition to the disease designated as familial pancreatic cancer (FPC), suggesting genetic modulation of FPC pathogenesis. It is estimated that currently identified sequence variants account for less than 20% of the genetic basis of FPC leaving the majority of the genetic architecture unclarified. We performed whole genome sequencing (WGS) analysis on benign formalin-fixed paraffin-embedded (FFPE) tissues from 35 FPC patients focusing on genes enriched by rare and functional sequence variants. We identified 40 genes hosting at least 2 protein truncating variants (PTVs). Significant overlaps of the 40 genes were found (p < 1 × 10–22) with cancer genes, cancer driver genes and genes found in previous studies on cancer, including ATM, POLE, BRCA2, TYR03, PABPC1 and SSC5D. The PTV genes are significantly overrepresented in biological pathways in cancer development and progression including extracellular matrix organization, signaling by RHO GTPases and RHO GTPase cycle. Association analysis using external controls detected 6 genes with p < 0.05. The WGS analysis revealed high heterogeneity in the detected rare variants among FPC patients and provides novel genes harboring potential mutational hotspots for future validation and replication.

Tan, M., Brusgaard, K., Gerdes, A-M., Larsen, M. J., Mortensen, M. B., Detlefsen, S., de Muckadell, O. B. S., & Joergensen, M. T. (2022). Whole genome sequencing identifies rare genetic variants in familial pancreatic cancer patients. Annals of Human Genetics, 1–12.

Complex Autism Spectrum Disorder with Epilepsy, Strabismus and Self-Injurious Behaviors in a Patient with a De Novo Heterozygous POLR2A Variant

Autism spectrum disorder (ASD) describes a complex and heterogenous group of neurodevelopmental disorders. Whole genome sequencing continues to shed light on the multifactorial etiology of ASD. Dysregulated transcriptional pathways have been implicated in neurodevelopmental disorders. Emerging evidence suggests that de novo POLR2A variants cause a newly described phenotype called ‘Neurodevelopmental Disorder with Hypotonia and Variable Intellectual and Behavioral Abnormalities’ (NEDHIB). The variable phenotype manifests with a spectrum of features; primarily early onset hypotonia and delay in developmental milestones. In this study, we investigate a patient with complex ASD involving epilepsy and strabismus. Whole genome sequencing of the proband–parent trio uncovered a novel de novo POLR2A variant (c.1367T>C, p. Val456Ala) in the proband. The variant appears deleterious according to in silico tools. We describe the phenotype in our patient, who is now 31 years old, draw connections between the previously reported phenotypes and further delineate this emerging neurodevelopmental phenotype. This study sheds new insights into this neurodevelopmental disorder, and more broadly, the genetic etiology of ASD.

Evans, D.R.; Qiao, Y.; Trost, B.; Calli, K.; Martell, S.; Jones, S.J.M.; Scherer, S.W.; Lewis, M.E.S. Complex Autism Spectrum Disorder with Epilepsy, Strabismus and Self-Injurious Behaviors in a Patient with a De Novo Heterozygous POLR2A Variant. Genes 2022, 13, 470.

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