A recurrent synonymous KAT6B mutation causes Say-Barber-Biesecker/Young-Simpson syndrome by inducing aberrant splicing.
Mutations of the histone acetyltransferase-encoding KAT6B gene cause the Say-Barber-Biesecker/Young-Simpson (SBBYS) type of blepharophimosis-"mental retardation" syndromes and the more severe genitopatellar syndrome. The SBBYS syndrome-causing mutations are clustered in the large exon 18 of KAT6B and almost exclusively lead to predicted protein truncation. An atypical KAT6B mutation, a de novo synonymous variant located in exon 16 (c.3147G>A, p.(Pro1049Pro)) was previously identified in three unrelated patients. This exonic mutation was predicted in silico to cause protein truncation through aberrant splicing. Here, we report three additional unrelated children with typical SBBYS syndrome and the KAT6B c.3147G>A mutation. We show on RNA derived from patient blood that the mutation indeed induces aberrant splicing through the use of a cryptic exonic splice acceptor site created by the sequence variant. Our results thus identify the synonymous variant c.3147G>A as a splice site mutation and a mutational hot spot in SBBYS syndrome.
Institute of Human Genetics, University of Ulm, Ulm, Germany.|International Graduate School in Molecular Medicine Ulm, University of Ulm, Ulm, Germany.
Rüstem
R
Yilmaz
Medical Genetics Department, Hospital Pedi, á, trico, Centro Hospitalar e Universitario de Coimbra, Coimbra, Portugal.|Department of Clinical Genetics, Guy's Hospital, London, UK.
Ana
A
Beleza-Meireles
Department of Clinical Genetics, Northampton General Hospital, NHS Trust, Northampton, UK.
Susan
S
Price
Medical Genetics Department, Hospital Pedi, á, trico, Centro Hospitalar e Universitario de Coimbra, Coimbra, Portugal.
Renata
R
Oliveira
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Christian
C
Kubisch
Manchester Centre for Genomic Medicine, Central Manchester University Hospitals, NHS Foundation Trust, Saint Mary's Hospital, Manchester, UK.
Jill
J
Clayton-Smith
Institute of Pediatrics, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
Katalin
K
Szakszon
Institute of Human Genetics, University of Ulm, Ulm, Germany.
Guntram
G
Borck
D016569:Blepharophimosis / Q000209:etiology / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003409:Congenital Hypothyroidism / Q000209:etiology / Q000235:genetics*; D019066:Facies; D005260:Female; D006330:Heart Defects, Congenital / Q000209:etiology / Q000235:genetics*; D051548:Histone Acetyltransferases / Q000235:genetics*; D006801:Humans; D008607:Intellectual Disability / Q000209:etiology / Q000235:genetics*; D007593:Joint Instability / Q000209:etiology / Q000235:genetics*; D008297:Male; D009154:Mutation; D011247:Pregnancy; D022821:RNA Splice Sites; D012326:RNA Splicing
D022821:RNA Splice Sites; D051548:Histone Acetyltransferases; C487137:KAT6B protein, human
KAT6B; Ohdo syndrome; Say-Barber-Biesecker syndrome; Young-Simpson syndrome; recurrent mutation