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Eur J Hum Genet. 2015 Sep;23(9):1165-70. doi: 10.1038/ejhg.2014.248. Epub 2014 Nov 26.

Further delineation of the KAT6B molecular and phenotypic spectrum.

Author information

1
Manchester Centre For Genomic Medicine, University of Manchester, St Mary's Hospital, Manchester Academic Health Science Centre, Manchester, UK.
2
Department of Clinical Genetics, City Hospital, Nottingham, UK.
3
Centre for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
4
Genetic Health Queensland and University of Queensland. Royal Brisbane and Women's Hospital, PO Box Herston QLD, Australia.
5
Department of Clinical Genetics, Children's Hospital at Westmead, Sydney, Australia.
6
Département de Génétique, Université Paris Descartes-Sorbonne Paris Cité, INSERM UMR 1163, Imagine Institute, Hôpital Necker Enfants Malades, AP-HP, 24, boulevard de Montparnasse, Paris.
7
Institute of Human Genetics, University of Ulm, Ulm, Germany.
8
Institut fur Humangenetik, Universitätsklinikum Essen, Essen, Germany.
9
Institute of Molecular Medicine and Surgery, Centre for Molecular Medicine, Karolinska Institut and Clinical Genetic Department, Karolinska University Hospital, Stockholm, Sweden.
10
Clinical Genetics, University Hospitals, Bristol, UK.
11
Clinical Genetics, Birmingham Women's Hospital NHS Foundation Trust, Birmingham, UK.
12
Clinical Genetics, Hacettepe University, Ihsan Dogramaci Children's Hospital, Ankara, Turkey.
13
Centre de Génétique Humaine, Institut de Pathologie et de Génétique, Gosselies, Belgium.
14
Division of Genetics, Birth Defects and Metabolism, Children's Hospital of Chicago, Chicago, IL, USA.
15
Clinical Genetics, Guys Hospital, Great Maze Pond, London.
16
North West Thames Regional Genetics Service, North West London Hospitals NHS Trust, Harrow, UK.
17
Clinical Genetics, Northampton General Hospital, Cliftonville, Northampton, England.
18
Paediatrics and Medical Genetics, Barzilai Medical Centre, Ashkelon, Israel.
19
Center for Human Genetics, Clinique Universitaire St-Luc, Université Catholique de Louvain, Brussels, Belgium.
20
Service de Génétique, Centre Hospitalier Universitaire, Tours, France.
21
Service de Génétique Medicale CHU Rennes, Université de Rennes, Rennes, France.
22
Department of Pediatric Genetics, Cerrahpaşa Medical School, Istanbul University, Istanbul, Turkey.
23
Clinical Genetics, Birmingham Women's Hospital, Birmingha, UK.
24
Department of Genetics, University of Groningen, University Medical Centre, Groningen, The Netherlands.
25
Medical Genetics, Belfast City Hospital, Belfast, Northern Ireland.
26
Centre For Medical Genetics, Prins Boudewijnlaan 43, Edegem, Belgium.
27
Clinical Genetic Service, Department of Health, Hong Kong, China.
28
Institute of Medical Genetics, University Hospital of Wales, Cardif, Wales.
29
National Centre For Medical Genetics, Our Lady's Hospital For Sick Children, Dublin, Ireland.
30
Clinical Genetics Unit, Obstetric and Pediatric Department, Arcispedale S. Maria Nuova, Istitu di Ricovero e Cura a Carattere Scientifico, Reggio, Emilia, Italy.
31
Institute of Human Genetics, University of Pavia, Pavia, Italy.
32
UZ Leuven, Campus Gasthuisberg, Leuven, Belgium.
33
East Anglian Medical Genetics Service, Addenbrookes Hospital, Cambridge, MA, USA.
34
Department of Clinical Genetics, Sheffield Children's Hospital, Sheffield, UK.
35
Service de Génétique, HMB-CHU Reims, Reims, France.
36
Leiden University Medical Centre, Leiden, The Netherlands.
37
Service de Génétique Médicale, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
38
Centre For Human Genetics, Freiburg, Germany.

Abstract

KAT6B sequence variants have been identified previously in both patients with the Say-Barber-Biesecker type of blepharophimosis mental retardation syndromes (SBBS) and in the more severe genitopatellar syndrome (GPS). We report on the findings in a previously unreported group of 57 individuals with suggestive features of SBBS or GPS. Likely causative variants have been identified in 34/57 patients and were commonly located in the terminal exons of KAT6B. Of those where parental samples could be tested, all occurred de novo. Thirty out of thirty-four had truncating variants, one had a missense variant and the remaining three had the same synonymous change predicted to affect splicing. Variants in GPS tended to occur more proximally to those in SBBS patients, and genotype/phenotype analysis demonstrated significant clinical overlap between SBBS and GPS. The de novo synonymous change seen in three patients with features of SBBS occurred more proximally in exon 16. Statistical analysis of clinical features demonstrated that KAT6B variant-positive patients were more likely to display hypotonia, feeding difficulties, long thumbs/great toes and dental, thyroid and patella abnormalities than KAT6B variant-negative patients. The few reported patients with KAT6B haploinsufficiency had a much milder phenotype, though with some features overlapping those of SBBS. We report the findings in a previously unreported patient with a deletion of the KAT6B gene to further delineate the haploinsufficiency phenotype. The molecular mechanisms giving rise to the SBBS and GPS phenotypes are discussed.

PMID:
25424711
PMCID:
PMC4351891
DOI:
10.1038/ejhg.2014.248
[Indexed for MEDLINE]
Free PMC Article

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