Dominant mutations in KAT6A cause intellectual disability with recognizable syndromic features

Am J Hum Genet. 2015 Mar 5;96(3):507-13. doi: 10.1016/j.ajhg.2015.01.016.

Emma Tham ¹, Anna Lindstrand ², Avni Santani ³, Helena Malmgren ², Addie Nesbitt ⁴, Holly A Dubbs ⁵, Elaine H Zackai ⁵, Michael J Parker ⁶, Francisca Millan ⁷, Kenneth Rosenbaum ⁸, Golder N Wilson ⁹, Ann Nordgren ²

Affiliations

1 Department of Clinical Genetics, Karolinska University Hospital, 171 76 Stockholm, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden. Electronic address: emma.tham@karolinska.se.
2 Department of Clinical Genetics, Karolinska University Hospital, 171 76 Stockholm, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden.
3 Division of Genomic Diagnostics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA.
4 Division of Genomic Diagnostics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
5 Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
6 Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield S10 2TH, UK.
7 GeneDx Laboratory, Gaithersburg, MD 20877, USA.
8 Division of Genetics and Metabolism, Children's National Medical Center, Washington, DC 20010, USA.
9 Department of Pediatrics, Texas Tech University Health Science Center, Lubbock, TX 79106, and Medical City Hospital, Dallas, TX 75230, USA; KinderGenome Pediatric Genetics, Medical City Hospital, Dallas, TX 75230, USA.

PMID: 25728777 DOI: 10.1016/j.ajhg.2015.01.016

Abstract

Through a multi-center collaboration study, we here report six individuals from five unrelated families, with mutations in KAT6A/MOZ detected by whole-exome Sequencing. All five different de novo heterozygous truncating mutations were located in the C-terminal transactivation domain of KAT6A: NM_001099412.1: c.3116_3117 delCT, p.(Ser1039∗); c.3830_3831insTT, p.(Arg1278Serfs∗17); c.3879 dupA, p.(Glu1294Argfs∗19); c.4108G>T p.(Glu1370∗) and c.4292 dupT, p.(Leu1431Phefs∗8). An additional subject with a 0.23 MB microdeletion including the entire KAT6A reading frame was identified with genome-wide array comparative genomic hybridization. Finally, by detailed clinical characterization we provide evidence that heterozygous mutations in KAT6A cause a distinct intellectual disability syndrome. The common phenotype includes hypotonia, intellectual disability, early feeding and oromotor difficulties, microcephaly and/or craniosynostosis, and cardiac defects in combination with subtle facial features such as bitemporal narrowing, broad nasal tip, thin upper lip, posteriorly rotated or low-set ears, and microretrognathia. The identification of human subjects complements previous work from mice and zebrafish where knockouts of Kat6a/kat6a lead to developmental defects.

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