Novel KDM6A (UTX) mutations and a clinical and molecular review of the X‐linked Kabuki syndrome (KS2) |
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| Authors: | V. Benoit E. Jenkins E. Howard S. Bunstone B. Kerr S. McKee I.C. Lloyd D. Shears H. Stewart S.M. White R. Savarirayan G.M.S. Mancini D. Beysen R.D. Cohn B. Grisart I. Maystadt D. Donnai |
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| Affiliation: | 1. Centre de Génétique Humaine, Institut de Pathologie et Génétique, Charleroi, Belgium;2. Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester Academic Health Science Centre (MAHSC), Manchester, UK;3. Manchester Centre for Genomic Medicine, Institute of Human Development, University of Manchester, Manchester, UK;4. Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, UK;5. Manchester Royal Eye Hospital, MAHSC, Manchester, UK;6. Department of Clinical Genetics, Churchill Hospital, Oxford University Hospitals NHS Trust, Oxford, UK;7. Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia;8. Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia;9. Department of Clinical Genetics, Erasmus University Medical Center (Erasmus MC), Rotterdam, The Netherlands;10. Center for Medical Genetics, Ghent University, Ghent, Belgium;11. Department of Paediatrics and Molecular Genetics, The Hospital for Sick Children, University of Toronto, Toronto, Canada |
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| Abstract: | We describe seven patients with KDM6A (located on Xp11.3 and encodes UTX) mutations, a rare cause of Kabuki syndrome (KS2, MIM 300867) and report, for the first time, germ‐line missense and splice‐site mutations in the gene. We demonstrate that less than 5% cases of Kabuki syndrome are due to KDM6A mutations. Our work shows that similar to the commoner Type 1 Kabuki syndrome (KS1, MIM 147920) caused by KMT2D (previously called MLL2) mutations, KS2 patients are characterized by hypotonia and feeding difficulties during infancy and poor postnatal growth and short stature. Unlike KS1, developmental delay and learning disability are generally moderate–severe in boys but mild–moderate in girls with KS2. Some girls may have a normal developmental profile. Speech and cognition tend to be more severely affected than motor development. Increased susceptibility to infections, join laxity, heart, dental and ophthalmological anomalies are common. Hypoglycaemia is more common in KS2 than in KS1. Facial dysmorphism with KDM6A mutations is variable and diagnosis on facial gestalt alone may be difficult in some patients. Hypertrichosis, long halluces and large central incisors may be useful clues to an underlying KDM6A mutation in some patients. |
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| Keywords: | Kabuki syndrome KDM6A KMT2D MLL2 UTX |
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