Biallelic loss-of-function P4HTM gene variants cause hypotonia,hypoventilation, intellectual disability,dysautonomia, epilepsy,and eye abnormalities (HIDEA syndrome) |
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| Affiliation: | 1. PEDEGO Research Unit and Medical Research Centre Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland;2. Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland;3. Biocenter Oulu, University of Oulu, Oulu, Finland;4. Faculty of Biochemistry and Molecular Medicine, Oulu Centre for Cell-Matrix Research, University of Oulu, Oulu, Finland;5. Department of Children and Adolescents, Division of Paediatric Neurology, Oulu University Hospital, Oulu, Finland;6. Kaiser Franz Josef Hospital with G.v. Preyer Children’s Hospital, Department of Pediatrics, Vienna, Austria;7. Department of Clinical Genetics, Amsterdam UMC, University oF.A.msterdam, Amsterdam, The Netherlands;8. Neuromuscular Research Department, Medical University of Vienna, Centre for Anatomy and Cell Biology, Vienna, Austria;9. Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA;10. The Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA;11. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland;12. Texas Children’s Hospital, Houston, TX, USA;13. Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA;14. Northern Finland Laboratory Centre Nord, Lab and Medical Research Centre, Oulu University Hospital and University of Oulu, Oulu, Finland;15. Department of Pathology, Oulu University Hospital, Oulu, Finland;16. Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA;17. Department of Neurology, Massachusetts General Hospital, Boston, MA, USA;18. Department of Medical Genetics, Genome-Scale Biology Research Program, University of Helsinki and Haartman Institute, Helsinki, Finland;19. Baylor Genetics, 77021, Houston, TX, USA;1. PEDEGO Research Unit and Medical Research Centre Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland;2. Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland;3. Biocenter Oulu, University of Oulu, Oulu, Finland;4. Faculty of Biochemistry and Molecular Medicine, Oulu Centre for Cell-Matrix Research, University of Oulu, Oulu, Finland;5. Department of Children and Adolescents, Division of Paediatric Neurology, Oulu University Hospital, Oulu, Finland;6. Kaiser Franz Josef Hospital with G.v. Preyer Children’s Hospital, Department of Pediatrics, Vienna, Austria;7. Department of Clinical Genetics, Amsterdam UMC, University oF.A.msterdam, Amsterdam, The Netherlands;8. Neuromuscular Research Department, Medical University of Vienna, Centre for Anatomy and Cell Biology, Vienna, Austria;9. Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA;10. The Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA;11. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland;12. Texas Children’s Hospital, Houston, TX, USA;13. Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA;14. Northern Finland Laboratory Centre Nord, Lab and Medical Research Centre, Oulu University Hospital and University of Oulu, Oulu, Finland;15. Department of Pathology, Oulu University Hospital, Oulu, Finland;16. Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA;17. Department of Neurology, Massachusetts General Hospital, Boston, MA, USA;18. Department of Medical Genetics, Genome-Scale Biology Research Program, University of Helsinki and Haartman Institute, Helsinki, Finland;19. Baylor Genetics, 77021, Houston, TX, USA |
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| Abstract: | PurposeA new syndrome with hypotonia, intellectual disability, and eye abnormalities (HIDEA) was previously described in a large consanguineous family. Linkage analysis identified the recessive disease locus, and genome sequencing yielded three candidate genes with potentially pathogenic biallelic variants: transketolase (TKT), transmembrane prolyl 4-hydroxylase (P4HTM), and ubiquitin specific peptidase 4 (USP4). However, the causative gene remained elusive.MethodsInternational collaboration and exome sequencing were used to identify new patients with HIDEA and biallelic, potentially pathogenic, P4HTM variants. Segregation analysis was performed using Sanger sequencing. P4H-TM wild-type and variant constructs without the transmembrane region were overexpressed in insect cells and analyzed using sodium dodecyl sulfate–polyacrylamide gel electrophoresis and western blot.ResultsFive different homozygous or compound heterozygous pathogenic P4HTM gene variants were identified in six new and six previously published patients presenting with HIDEA. Hypoventilation, obstructive and central sleep apnea, and dysautonomia were identified as novel features associated with the phenotype. Characterization of three of the P4H-TM variants demonstrated yielding insoluble protein products and, thus, loss-of-function.ConclusionsBiallelic loss-of-function P4HTM variants were shown to cause HIDEA syndrome. Our findings enable diagnosis of the condition, and highlight the importance oF.A.ssessing the need for noninvasive ventilatory support in patients. |
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