Clinical utility of whole-exome sequencing in rare diseases: Galactosialidosis |
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| Affiliation: | 1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA;2. Department of Molecular and Human Genetics, Texas Children''s Hospital, Houston, TX, USA;1. Metabolic Research, Murdoch Childrens Research Institute, and Victorian Clinical Genetics Services, Royal Children''s Hospital, Melbourne, Australia;2. Radboud University Medical Centre, Nijmegen, The Netherlands;3. Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia;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. Department of Genetics, Health Research Institute–Jimenez Diaz Foundation University Hospital (IIS-FJD), Universidad Autónoma de Madrid, Spain;2. Department of Clinical Analysis, Hospital Universitario Clínico San Carlos, Madrid, Spain;3. CIBERER (Centro de Investigación Biomédica en Red de Enfermedades Raras), Instituto de Salud Carlos III, Madrid, Spain;4. Diabetes, Nephrology and Vascular Pathology Research Laboratory, Health Research Institute–Jimenez Diaz Foundation University Hospital (IIS-FJD), Universidad Autónoma de Madrid, Spain |
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| Abstract: | Rare genetic disorders can go undiagnosed for years as the entire spectrum of phenotypic variation is not well characterized given the reduced number of patients reported in the literature and the low frequency at which these occur. Moreover, the current paradigm for clinical diagnostics defines disease diagnosis by a specified spectrum of phenotypic findings; when such parameters are either missing, or other findings not usually observed are seen, the phenotype driven approach to diagnosis may result in a specific etiological diagnosis not even being considered within the differential diagnosis. The novel implementation of genomic sequencing approaches to investigate rare genetic disorders is allowing not only the discovery of new genes, but also the phenotypic expansion of known Mendelian genetic disorders. Here we report the detailed clinical assessment of a patient with a rare genetic disorder with undefined molecular diagnosis. We applied whole-exome sequencing to this patient and unaffected parents in order to identify the molecular cause of her disorder. We identified compound heterozygous mutations in the CTSA gene, responsible for causing galactosialidosis; the molecular diagnosis was further confirmed by biochemical studies. This report expands on the clinical spectrum of this rare lysosomal disorder and exemplifies how genomic approaches are further elucidating the characterization and understanding of genetic diseases. |
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| Keywords: | Exome sequencing Galactosialidosis Protective protein cathepsin A |
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