Related Experiment Video
Updated: Jul 5, 2025
In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
Published on: August 20, 2019
Biallelic SOX8 Variants Associated With Novel Syndrome With Myopathy, Skeletal Deformities, Intellectual Disability,
Jodi Warman-Chardon1, Taila Hartley1, Aren Elizabeth Marshall1
1From the Department of Medicine (J.W.-C., P.R.B., A.B., H.L.), The Ottawa Hospital; The Ottawa Hospital Research Institute (J.W.-C., P.R.B., H.L., J.W., M.L.S., G.M.); Faculty of Medicine (J.W.-C., P.R.B., A.B., H.L., J.W., M.L.S., D.A.D., K.M.B.); Children's Hospital of Eastern Ontario Research Institute (J.W.-C., T.H., A.E.M., A.M., H.L., D.A.D., K.M.B., K.K.), University of Ottawa; Hospital for Sick Children (M.C.), Centre for Computational Medicine, Toronto, Canada; Department of Obstetrics (W.M., M.R.W.M.), Gynaecology and Reproductive Sciences, University of Pittsburgh School of Medicine; Magee-Womens Research Institute (W.M., M.R.W.M.), Pittsburgh, PA; Department of Pathology and Laboratory Medicine (A.B., J.W.), The Ottawa Hospital; Department of Radiology (M.L.S., G.M.), Radiation Oncology and Medical Physics, University of Ottawa; Department of Neurology and Neurosurgery (B.B.), Montreal Neurological Institute and Hospital, McGill University; and Newborn Screening Ontario (K.K.), Children's Hospital of Eastern Ontario, Ottawa, Canada.
Background And Objectives:
The human genome contains ∼20,000 genes, each of which has its own set of complex regulatory systems to govern precise expression in each developmental stage and cell type. Here, we report a female patient with congenital weakness, respiratory failure, skeletal dysplasia, contractures, short stature, intellectual delay, respiratory failure, and amenorrhea who presented to Medical Genetics service with no known cause for her condition.
Methods:
Whole-exome and whole-genome sequencing were conducted, as well as investigational functional studies to assess the effect of SOX8 variant.
Results:
The patient was found to have biallelic SOX8 variants (NM_014587.3:c.422+5G>C; c.583dup p.(His195ProfsTer11)). SOX8 is a transcriptional regulator, which is predicted to be imprinted (expressed from only one parental allele), but this has not yet been confirmed. We provide evidence that while SOX8 was maternally expressed in adult-derived fibroblasts and lymphoblasts, it was biallelically expressed in other cell types and therefore suggest that biallelic variants are associated with this recessive condition. Functionally, we showed that the paternal variant had the capacity to affect mRNA splicing while the maternal variant resulted in low levels of a truncated protein, which showed decreased binding at and altered expression of SOX8 targets.
Discussion:
Our findings associate SOX8 variants with this novel condition, highlight how complex genome regulation can complicate novel disease-gene identification, and provide insight into the molecular pathogenesis of this disease.
More Related Videos
09:37Navigating MARRVEL, a Web-Based Tool that Integrates Human Genomics and Model Organism Genetics Information
Published on: August 15, 2019
08:22A Novel Strategy Combining Array-CGH, Whole-exome Sequencing and In Utero Electroporation in Rodents to Identify Causative Genes for Brain Malformations
Published on: December 1, 2017
Related Concept Videos
01:33Pleiotropy
02:30Genomic Imprinting and Inheritance
The expression of some genes depends on which parent passed the gene to the offspring, through a phenomenon known as...
02:41Lethal Alleles
Lucien Cuénot discovered lethal alleles in 1905 while studying the inheritance of coat color in mice. The agouti gene is responsible for the color of the coat in mice. This gene codes for an agouti-signaling protein, which is responsible for melanin distribution in mammals. The wild-type allele gives rise to gray-brown coat color in mice, while the mutant allele gives rise to yellow coat color. In addition to coat color, the agouti gene is associated with the yellow...
03:14Notch Signaling Pathway
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not...
01:35Pedigree Analysis
01:32RNA Splicing