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Genetic Heterogeneity in Cornelia De Lange Syndrome (Cdls) and Cdls-Like Phenotypes With Observed and Predicted Levels of Mosaicism Publisher Pubmed



Ansari M1 ; Poke G1 ; Ferry Q2, 3 ; Williamson K1 ; Aldridge R1 ; Meynert AM1 ; Bengani H1 ; Chan CY1 ; Kayserili H4 ; Avci S4 ; Hennekam RCM5 ; Lampe AK6 ; Redeker E5 ; Homfray T7 Show All Authors
Authors
  1. Ansari M1
  2. Poke G1
  3. Ferry Q2, 3
  4. Williamson K1
  5. Aldridge R1
  6. Meynert AM1
  7. Bengani H1
  8. Chan CY1
  9. Kayserili H4
  10. Avci S4
  11. Hennekam RCM5
  12. Lampe AK6
  13. Redeker E5
  14. Homfray T7
  15. Ross A8
  16. Smeland MF9
  17. Mansour S7
  18. Parker MJ10
  19. Cook JA10
  20. Splitt M11
  21. Fisher RB11
  22. Fryer A12
  23. Magee AC13
  24. Wilkie A14
  25. Barnicoat A15
  26. Brady AF16
  27. Cooper NS17
  28. Mercer C18
  29. Deshpande C19
  30. Bennett CP20
  31. Pilz DT21
  32. Ruddy D19
  33. Cilliers D22
  34. Johnson DS10
  35. Josifova D19
  36. Rosser E15
  37. Thompson EM23, 24
  38. Wakeling E16
  39. Kinning E25
  40. Stewart F13
  41. Flinter F19
  42. Girisha KM26
  43. Cox H17
  44. Firth HV27
  45. Kingston H28
  46. Wee JS29
  47. Hurst JA15
  48. Claytonsmith J28
  49. Tolmie J25
  50. Vogt J17
  51. Tattonbrown K7
  52. Chandler K28
  53. Prescott K20
  54. Wilson L15
  55. Behnam M30
  56. Mcentagart M7
  57. Davidson R25
  58. Lynch SA31
  59. Sisodiya S32
  60. Mehta SG27
  61. Mckee SA13
  62. Mohammed S19
  63. Holden S27
  64. Park SM27
  65. Holder SE16
  66. Harrison V18
  67. Mcconnell V13
  68. Lam WK6
  69. Green AJ31, 33
  70. Donnai D28
  71. Bitnerglindzicz M15, 34
  72. Donnelly DE13
  73. Nellaker C3
  74. Taylor MS1
  75. Fitzpatrick DR1
Show Affiliations
Authors Affiliations
  1. 1. MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
  2. 2. Visual Geometry Group, Department of Engineering Science, University of Oxford, Oxford, United Kingdom
  3. 3. Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
  4. 4. Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey
  5. 5. Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
  6. 6. South East of Scotland Clinical Genetic Service, Molecular Medicine Centre, Western General Hospital, Edinburgh, United Kingdom
  7. 7. Medical Genetics Unit, St George's University of London, London, United Kingdom
  8. 8. North of Scotland Regional Genetics Service, Clinical Genetics Centre, Aberdeen, United Kingdom
  9. 9. Department of Medical Genetics, University Hospital of Northern Norway, Tromso, Norway
  10. 10. Sheffield Children's Hospital, NHS Foundation Trust, Sheffield, United Kingdom
  11. 11. Northern Genetics Service, Newcastle upon Tyne Hospitals, Newcastle upon Tyne, United Kingdom
  12. 12. Department of Clinical Genetics, Alder Hay Children's Hospital, Liverpool, United Kingdom
  13. 13. Northern Ireland Regional Genetics Service (NIRGS), Belfast City Hospital, Belfast, United Kingdom
  14. 14. Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
  15. 15. Clinical Genetics Department, Great Ormond Street Hospital, London, United Kingdom
  16. 16. North West Thames Regional Genetics Service, Kennedy-Galton Centre, North West London Hospitals NHS Trust, Harrow, United Kingdom
  17. 17. West Midlands Regional Clinical Genetics Service, Birmingham Women's Hospital, West Midlands, United Kingdom
  18. 18. Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, United Kingdom
  19. 19. Department of Genetics, Guy's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
  20. 20. Clinical Genetics, Yorkshire Regional Genetics Service, Leeds, United Kingdom
  21. 21. Institute of Medical Genetics, University Hospital of Wales, Cardiff, United Kingdom
  22. 22. Department of Clinical Genetics, The Churchill Hospital Old Road, Oxford, United Kingdom
  23. 23. SA Clinical Genetics Service, Women's and Children's Hospital, Adelaide, Australia
  24. 24. Department of Paediatrics, University of Adelaide, Adelaide, Australia
  25. 25. West of Scotland Regional Genetics Service, Ferguson-Smith Centre for Clinical Genetics, Yorkhill Hospital, Glasgow, United Kingdom
  26. 26. Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, India
  27. 27. Department of Medical Genetics, Cambridge University Addenbrooke's Hospital, Cambridge, United Kingdom
  28. 28. Faculty of Medical and Human Sciences, Manchester Centre for Genomic Medicine, Institute of Human Development, University of Manchester, Manchester Academic Health Science Centre (MAHSC), Manchester, United Kingdom
  29. 29. Department of Dermatology, Kingston Hospital NHS Trust, Surrey, United Kingdom
  30. 30. Medical Genetics Laboratory of Genome, Isfahan University of Medical Sciences, Isfahan, Iran
  31. 31. National Centre for Medical Genetics, Our Lady's Children's Hospital, Dublin 12, Ireland
  32. 32. Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, United Kingdom
  33. 33. School of Medicine and Medical Science, University College Dublin, Dublin 4, Ireland
  34. 34. Genetics and Genomic Medicine Programme, UCL Institute of Child Health, London, United Kingdom

Source: Journal of Medical Genetics Published:2014


Abstract

Background: Cornelia de Lange syndrome (CdLS) is a multisystem disorder with distinctive facial appearance, intellectual disability and growth failure as prominent features. Most individuals with typical CdLS have de novo heterozygous loss-of-function mutations in NIPBL with mosaic individuals representing a significant proportion. Mutations in other cohesin components, SMC1A, SMC3, HDAC8 and RAD21 cause less typical CdLS. Methods: We screened 163 affected individuals for coding region mutations in the known genes, 90 for genomic rearrangements, 19 for deep intronic variants in NIPBL and 5 had whole-exome sequencing. Results: Pathogenic mutations [including mosaic changes] were identified in: NIPBL 46 [3] (28.2%); SMC1A 5 [1] (3.1%); SMC3 5 [1] (3.1%); HDAC8 6 [0] (3.6%) and RAD21 1 [0] (0.6%). One individual had a de novo 1.3 Mb deletion of 1p36.3. Another had a 520 kb duplication of 12q13.13 encompassing ESPL1, encoding separase, an enzyme that cleaves the cohesin ring. Three de novo mutations were identified in ANKRD11 demonstrating a phenotypic overlap with KBG syndrome. To estimate the number of undetected mosaic cases we used recursive partitioning to identify discriminating features in the NIPBL-positive subgroup. Filtering of the mutation-negative group on these features classified at least 18% as 'NIPBL-like'. A computer composition of the average face of this NIPBL-like subgroup was also more typical in appearance than that of all others in the mutationnegative group supporting the existence of undetected mosaic cases. Conclusions: Future diagnostic testing in 'mutationnegative' CdLS thus merits deeper sequencing of multiple DNA samples derived from different tissues.
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