Dominant mutations in KAT6A cause intellectual disability with recognizable syndromic features.
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.
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.
Emma
E
Tham
Department of Clinical Genetics, Karolinska University Hospital, 171 76 Stockholm, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden.
Anna
A
Lindstrand
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.
Avni
A
Santani
Department of Clinical Genetics, Karolinska University Hospital, 171 76 Stockholm, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden.
Helena
H
Malmgren
Division of Genomic Diagnostics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Addie
A
Nesbitt
Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Holly A
HA
Dubbs
Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Elaine H
EH
Zackai
Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield S10 2TH, UK.
Michael J
MJ
Parker
GeneDx Laboratory, Gaithersburg, MD 20877, USA.
Francisca
F
Millan
Division of Genetics and Metabolism, Children's National Medical Center, Washington, DC 20010, USA.
Kenneth
K
Rosenbaum
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.
Golder N
GN
Wilson
Department of Clinical Genetics, Karolinska University Hospital, 171 76 Stockholm, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden.
Ann
A
Nordgren
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D055028:Comparative Genomic Hybridization; D059472:Exome; D005260:Female; D017353:Gene Deletion; D056426:Genetic Loci; D006579:Heterozygote; D051548:Histone Acetyltransferases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D008831:Microcephaly / Q000235:genetics; D009154:Mutation; D010375:Pedigree; D010641:Phenotype
D051548:Histone Acetyltransferases; C108712:KAT6A protein, human