Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder,apraxia, and insensitivity to pain |
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| Institution: | 1. Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.;2. Faculty of Medicine, University of Cologne, Cologne, Germany.;3. Institute of Human Genetics, University Hospital Cologne, Cologne, Germany.;4. Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA.;5. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.;6. Baylor Genetics Laboratory, Houston, TX, USA.;7. GeneDX, Gaithersburg, MD, USA.;8. Mission Fullerton Genetics Center, Asheville, NC, USA.;9. Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.;10. Genetics/Dysmorphology, Rady Children’s Hospital, San Diego, CA, USA.;11. Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.;12. Department of Psychiatry & Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.;13. Institute for Society and Genetics, UCLA, Los Angeles, CA, USA.;14. Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, Saint Louis, MO, USA.;15. Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Biomedicine West Wing, International Centre for Life, Times Square, Newcastle upon Tyne, UK.;16. INTEGRIS Pediatric Neurology, Oklahoma City, OK, USA;17. National Institutes of Health, Undiagnosed Diseases Program Clinical Site, Bethesda, MD, USA.;18. University of Washington and Seattle Children’s Hospital Clinical Site, Seattle, WA, USA.;19. Harvard-affiliated Boston Children’s Hospital, Massachusetts General Hospital, Brigham and Women’s Hospital, and Brigham Genomics Medicine Clinical Site, Boston, MA, USA.;20. Baylor College of Medicine, Clinical Site, Houston, TX, USA.;21. University of Utah Clinical Site, Salt Lake City, UT, USA.;22. Stanford University Clinical Site, Stanford, CA, USA.;23. University of Miami Clinical Site, Miami, FL, USA.;24. Washington University of Saint Louis, Clinical Site, Saint Louis, MO, USA.;25. Washington University of Saint Louis, Model Organism Screening Center, Saint Louis, MO, USA.;26. Children’s Hospital of Philadelphia or University of Pennsylvania Clinical Site, Philadelphia, PA, USA.;27. Vanderbilt University Clinical Site, Nashville, TN, USA.;28. University of California, Los Angeles, Clinical Site, Los Angeles, CA, USA.;29. University of Alabama Coordinating Center, Birmingham, AL, USA.;30. Duke University Clinical Site, Durham, NC, USA.;31. Mayo Clinic Metabolomics Core, Rochester, MN, USA.;32. Baylor Genetics Sequencing Core, Houston, TX, USA.;33. Harvard Medical School Coordinating Center, Boston, MA, USA.;34. Columbia University Clinical Site, New York City, NY, USA.;35. Baylor College of Medicine, Model Organism Screening Center, Houston, TX, USA.;36. University of Oregon, Model Organism Screening Center, Eugene, OR, USA. |
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| Abstract: | PurposeWe characterize the clinical and molecular phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder who carry heterozygous missense variants of the PRKAR1B gene, which encodes the R1β subunit of the cyclic AMP-dependent protein kinase A (PKA).MethodsVariants of PRKAR1B were identified by single- or trio-exome analysis. We contacted the families and physicians of the six individuals to collect phenotypic information, performed in vitro analyses of the identified PRKAR1B-variants, and investigated PRKAR1B expression during embryonic development.ResultsRecent studies of large patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B. In our cohort, de novo origin of the PRKAR1B variants could be confirmed in five of six individuals, and four carried the same heterozygous de novo variant c.1003C>T (p.Arg335Trp; NM_001164760). Global developmental delay, autism spectrum disorder, and apraxia/dyspraxia have been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C>T variant. PRKAR1B expression in the brain was demonstrated during human embryonal development. Additionally, in vitro analyses revealed altered basal PKA activity in cells transfected with variant-harboring PRKAR1B expression constructs.ConclusionOur study provides strong evidence for a PRKAR1B-related neurodevelopmental disorder. |
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