Phenotypic expansion of CACNA1C-associated disorders to include isolated neurological manifestations |
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| Institution: | 1. Division of Genetics and Genomics, Department of Pediatrics, Boston Children’s Hospital, Boston, MA, USA;2. Department of Neurology, Boston Children’s Hospital, Boston, MA, USA;3. Division of Medical Genetics, Department of Pediatrics, Duke Health, Durham, NC, USA;4. Department of Pharmacology, Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada;5. Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany;6. Institute for Genomic Medicine, Columbia University Medical Center, New York, NY, USA;7. Medigenome, Swiss Institute of Genomic Medicine, Geneva, Switzerland;8. Division of Genetic Medicine, Lausanne University Hospital, Lausanne, Switzerland;9. Pediatric Neurology Unit, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel-Hahsomer, Israel;10. Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel;11. CHU de Poitiers, Service de Génétique, EA3808 NEUVACOD, Poitiers, France;12. Department of Medical Genetics, Oslo University Hospital, Oslo, Norway;13. CHU d’Angers, Service de Pédiatrie, EA3808 NEUVACOD, Angers, France;14. Pediatric Cardiology Unit, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel-Hahsomer, Israel;15. Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, USA;16. Department of Paediatrics and Child Health, Red Cross War Memorial Children’s Hospital, University of Cape Town, Cape Town, SA, South Africa;17. Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO, USA;18. Service de Génétique Moléculaire et Génomique, CHU, Rennes, France;19. University of Rennes, CNRS, IGDR, UMR 6290, Rennes, France;20. The Danek Gertner Insitute of Human Genetics, Sheba Medical Center, Tel-Hahsomer, Israel;21. Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel-Hahsomer, Israel;22. Center for Pediatric Genomic Medicine, Children’s Mercy Hospital, Kansas City, MO, USA;23. Rare Diseases and Medical Genetic Unit, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy;24. Pediatric Neurology, Lausanne University Hospital, Lausanne, Switzerland;25. Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands;26. Unit of Neuromuscular and Neurodegenerative Diseases, Department of Neurosciences and Neurorehabilitation, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy;27. Service de Génétique Clinique, Centre de référence “Maladies Rares” Anomalies du développement CLAD-Ouest, Hôpital SUD, Échirolles, France;28. Center for Mendelian Genomics and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA;29. Division of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA;30. Instituto de Genética Médica y Molecular (INGEMM), Hospital Universitario La Paz, IdiPAZ, CIBERER, ISCIII, Madrid, Spain;31. Cincinnati Children’s Hospital and Medical Center Cincinnati, Cincinnati, OH, USA;32. University of Cincinnati College of Medicine Cincinnati, Cincinnati, OH, USA;33. Institute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland;34. Department of Ophthalmology, University of Basel, Basel, Switzerland;35. Division of Genomic Diagnostics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA;36. Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA;37. Institute of Rare Diseases, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel-Hahsomer, Israel;38. Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA;39. Service de Génétique Médicale, CHU Nantes, France; Inserm, CNRS, Univ Nantes, l’institut du thorax, Nantes, France;40. Cardiovascular Research Institute, Weill Cornell Medicine, New York, NY, USA;41. The Saxon Epilepsy Center Kleinwachau, Radeberg, Germany;42. The Children’s Mercy Hospital, Kansas City, MO, USA;43. Department of Pediatrics University of Missouri—Kansas City, Kansas City, MO, USA;44. Department of Internal Medicine, University of Kansas Medical Center, Kansas City, MO, USA;45. Alberta Children’s Hospital Research Institute, Department of Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada;46. BCM Clinical, Houston, TX, USA;47. BCM MOSC, Houston, TX, USA;48. BCM Sequencing, Houston, TX, USA;49. CHOP, Philadelphia, PA, USA;50. Columbia University, New York, NY, USA;51. Duke University, Durham, NC, USA;52. Harvard University, Boston, MA, USA;53. Harvard CC, Boston, MA, USA;54. Mayo Clinic, Rochester, MN, USA;55. Miami, Miami, FL, USA;56. NIH, Bethesda, MD, USA;57. NIH UDP, Bethesda, MD, USA;58. NIH UDP, DRM, Bethesda, MD, USA;59. NIH UDP, NHGRI, Bethesda, MD, USA;60. PNW, Seattle, WA, USA;61. Stanford, Stanford, CA, USA;62. UAB CC, Birmingham, AL, USA;63. UCLA, Los Angeles, CA, USA;64. University of Utah, Salt Lake City, UT, USA;65. University of Utah/ARUP, Salt Lake City, UT, USA;66. UO MOSC, Eugene, OR, USA;67. Vanderbilt, Nashville, TN, USA;68. Washington University Clinical, St. Louis, MO, USA;1. Division of Genetics and Genomics, Department of Pediatrics, Boston Children’s Hospital, Boston, MA, USA;2. Department of Neurology, Boston Children’s Hospital, Boston, MA, USA;3. Division of Medical Genetics, Department of Pediatrics, Duke Health, Durham, NC, USA;4. Department of Pharmacology, Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada;5. Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany;6. Institute for Genomic Medicine, Columbia University Medical Center, New York, NY, USA;7. Medigenome, Swiss Institute of Genomic Medicine, Geneva, Switzerland;8. Division of Genetic Medicine, Lausanne University Hospital, Lausanne, Switzerland;9. Pediatric Neurology Unit, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel-Hahsomer, Israel;10. Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel;11. CHU de Poitiers, Service de Génétique, EA3808 NEUVACOD, Poitiers, France;12. Department of Medical Genetics, Oslo University Hospital, Oslo, Norway;13. CHU d’Angers, Service de Pédiatrie, EA3808 NEUVACOD, Angers, France;14. Pediatric Cardiology Unit, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel-Hahsomer, Israel;15. Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, USA;16. Department of Paediatrics and Child Health, Red Cross War Memorial Children’s Hospital, University of Cape Town, Cape Town, SA, South Africa;17. Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO, USA;18. Service de Génétique Moléculaire et Génomique, CHU, Rennes, France;19. University of Rennes, CNRS, IGDR, UMR 6290, Rennes, France;20. The Danek Gertner Insitute of Human Genetics, Sheba Medical Center, Tel-Hahsomer, Israel;21. Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel-Hahsomer, Israel;22. Center for Pediatric Genomic Medicine, Children’s Mercy Hospital, Kansas City, MO, USA;23. Rare Diseases and Medical Genetic Unit, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy;24. Pediatric Neurology, Lausanne University Hospital, Lausanne, Switzerland;25. Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands;26. Unit of Neuromuscular and Neurodegenerative Diseases, Department of Neurosciences and Neurorehabilitation, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy;27. Service de Génétique Clinique, Centre de référence “Maladies Rares” Anomalies du développement CLAD-Ouest, Hôpital SUD, Échirolles, France;28. Center for Mendelian Genomics and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA;29. Division of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA;30. Instituto de Genética Médica y Molecular (INGEMM), Hospital Universitario La Paz, IdiPAZ, CIBERER, ISCIII, Madrid, Spain;31. Cincinnati Children’s Hospital and Medical Center Cincinnati, Cincinnati, OH, USA;32. University of Cincinnati College of Medicine Cincinnati, Cincinnati, OH, USA;33. Institute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland;34. Department of Ophthalmology, University of Basel, Basel, Switzerland;35. Division of Genomic Diagnostics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA;36. Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA;37. Institute of Rare Diseases, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel-Hahsomer, Israel;38. Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA;39. Service de Génétique Médicale, CHU Nantes, France; Inserm, CNRS, Univ Nantes, l’institut du thorax, Nantes, France;40. Cardiovascular Research Institute, Weill Cornell Medicine, New York, NY, USA;41. The Saxon Epilepsy Center Kleinwachau, Radeberg, Germany;42. The Children’s Mercy Hospital, Kansas City, MO, USA;43. Department of Pediatrics University of Missouri—Kansas City, Kansas City, MO, USA;44. Department of Internal Medicine, University of Kansas Medical Center, Kansas City, MO, USA;45. Alberta Children’s Hospital Research Institute, Department of Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada;46. BCM Clinical, Houston, TX, USA;47. BCM MOSC, Houston, TX, USA;48. BCM Sequencing, Houston, TX, USA;49. CHOP, Philadelphia, PA, USA;50. Columbia University, New York, NY, USA;51. Duke University, Durham, NC, USA;52. Harvard University, Boston, MA, USA;53. Harvard CC, Boston, MA, USA;54. Mayo Clinic, Rochester, MN, USA;55. Miami, Miami, FL, USA;56. NIH, Bethesda, MD, USA;57. NIH UDP, Bethesda, MD, USA;58. NIH UDP, DRM, Bethesda, MD, USA;59. NIH UDP, NHGRI, Bethesda, MD, USA;60. PNW, Seattle, WA, USA;61. Stanford, Stanford, CA, USA;62. UAB CC, Birmingham, AL, USA;63. UCLA, Los Angeles, CA, USA;64. University of Utah, Salt Lake City, UT, USA;65. University of Utah/ARUP, Salt Lake City, UT, USA;66. UO MOSC, Eugene, OR, USA;67. Vanderbilt, Nashville, TN, USA;68. Washington University Clinical, St. Louis, MO, USA |
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| Abstract: | PurposeCACNA1C encodes the alpha-1-subunit of a voltage-dependent L-type calcium channel expressed in human heart and brain. Heterozygous variants in CACNA1C have previously been reported in association with Timothy syndrome and long QT syndrome. Several case reports have suggested that CACNA1C variation may also be associated with a primarily neurological phenotype.MethodsWe describe 25 individuals from 22 families with heterozygous variants in CACNA1C, who present with predominantly neurological manifestations.ResultsFourteen individuals have de novo, nontruncating variants and present variably with developmental delays, intellectual disability, autism, hypotonia, ataxia, and epilepsy. Functional studies of a subgroup of missense variants via patch clamp experiments demonstrated differential effects on channel function in vitro, including loss of function (p.Leu1408Val), neutral effect (p.Leu614Arg), and gain of function (p.Leu657Phe, p.Leu614Pro). The remaining 11 individuals from eight families have truncating variants in CACNA1C. The majority of these individuals have expressive language deficits, and half have autism.ConclusionWe expand the phenotype associated with CACNA1C variants to include neurodevelopmental abnormalities and epilepsy, in the absence of classic features of Timothy syndrome or long QT syndrome. |
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