Biallelic SOX8 Variants Associated With Novel Syndrome With Myopathy, Skeletal Deformities, Intellectual Disability, and Ovarian Dysfunction.

Autor:	Warman-Chardon J; From 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., Hartley T; From 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., Marshall AE; From 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., McBride A; From 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., Couse M; From 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., Macdonald W; From 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., Mann MRW; From 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., Bourque PR; From 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., Breiner A; From 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., Lochmüller H; From 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., Woulfe J; From 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., Sampaio ML; From 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., Melkus G; From 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., Brais B; From 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., Dyment DA; From 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., Boycott KM; From 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., Kernohan K; From 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.
Jazyk:	angličtina
Zdroj:	Neurology. Genetics [Neurol Genet] 2023 Sep 19; Vol. 9 (5), pp. e200088. Date of Electronic Publication: 2023 Sep 19 (Print Publication: 2023).
DOI:	10.1212/NXG.0000000000200088
Abstrakt:	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. Competing Interests: The authors report no relevant disclosures. Go to Neurology.org/NG for full disclosures (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)
Databáze:	MEDLINE
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