A recurrent synonymous KAT6B mutation causes Say-Barber-Biesecker/Young-Simpson syndrome by inducing aberrant splicing

American Journal of Medical Genetics. Part a
Rüstem YilmazGuntram Borck

Abstract

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.

References

Feb 1, 1988·Human Genetics·D N Cooper, H Youssoufian
Jan 24, 2012·American Journal of Human Genetics·Philippe M CampeauBrendan H Lee
Jan 24, 2012·American Journal of Human Genetics·Michael A SimpsonRichard C Trembath
Nov 27, 2014·European Journal of Human Genetics : EJHG·Tamsin GannonJill Clayton-Smith

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Citations

Jul 12, 2017·American Journal of Medical Genetics. Part a·Rani A BashirPing-Yee B Au
Dec 25, 2019·Human Genome Variation·Yo HamaguchiSumito Dateki
May 20, 2020·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Li Xin ZhangPhilippe M Campeau

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