title: NAA10 mutation causing a novel intellectual disability syndrome with Long QT due to N-terminal acetyltransferase impairment.
abstract: We report two brothers from a non-consanguineous Irish family presenting with a novel syndrome characterised by intellectual disability, facial dysmorphism, scoliosis and long QT. Their mother has a milder phenotype including long QT. X-linked inheritance was suspected. Whole exome sequencing identified a novel missense variant (c.128 A > C; p.Tyr43Ser) in NAA10 (X chromosome) as the cause of the family's disorder. Sanger sequencing confirmed that the mutation arose de novo in the carrier mother. NAA10 encodes the catalytic subunit of the major human N-terminal acetylation complex NatA. In vitro assays for the p.Tyr43Ser mutant enzyme showed a significant decrease in catalytic activity and reduced stability compared to wild-type Naa10 protein. NAA10 has previously been associated with Ogden syndrome, Lenz microphthalmia syndrome and non-syndromic developmental delay. Our findings expand the clinical spectrum of NAA10 and suggest that the proposed correlation between mutant Naa10 enzyme activity and phenotype severity is more complex than anticipated; the p.Tyr43Ser mutant enzyme has less catalytic activity than the p.Ser37Pro mutant associated with lethal Ogden syndrome but results in a milder phenotype. Importantly, we highlight the need for cardiac assessment in males and females with NAA10 variants as both patients and carriers can have long QT.
authors.affiliation: Clinical Genetics, Temple Street Children's University Hospital, Temple Street, Dublin 1, Ireland.|UCD Academic Centre on Rare Diseases, School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland.
authors.forename: Jillian P
authors.initials: JP
authors.lastname: Casey
authors.affiliation: Department of Molecular Biology, University of Bergen, Norway.
authors.forename: Svein I
authors.initials: SI
authors.lastname: Støve
authors.affiliation: Department of Cardiology, Mater Misericordiae University Hospital, Eccles Street, Dublin 7, Ireland.|School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland.
authors.forename: Catherine
authors.initials: C
authors.lastname: McGorrian
authors.affiliation: Department of Cardiology, Mater Misericordiae University Hospital, Eccles Street, Dublin 7, Ireland.
authors.forename: Joseph
authors.initials: J
authors.lastname: Galvin
authors.affiliation: Department of Molecular Biology, University of Bergen, Norway.
authors.forename: Marina
authors.initials: M
authors.lastname: Blenski
authors.affiliation: UCD Academic Centre on Rare Diseases, School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland.
authors.forename: Aimee
authors.initials: A
authors.lastname: Dunne
authors.affiliation: UCD Academic Centre on Rare Diseases, School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland.
authors.forename: Sean
authors.initials: S
authors.lastname: Ennis
authors.affiliation: Department of Neuropathology, Beaumont Hospital, Dublin 9, Ireland.
authors.forename: Francesca
authors.initials: F
authors.lastname: Brett
authors.affiliation: Department of Paediatric Neurology &Clinical Neurophysiology, Temple Street Children's University Hospital, Dublin 1, Ireland.|UCD Academic Centre on Rare Diseases, School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland.
authors.forename: Mary D
authors.initials: MD
authors.lastname: King
authors.affiliation: Department of Molecular Biology, University of Bergen, Norway.|Department of Surgery, Haukeland University Hospital, Norway.
authors.forename: Thomas
authors.initials: T
authors.lastname: Arnesen
authors.affiliation: Clinical Genetics, Temple Street Children's University Hospital, Temple Street, Dublin 1, Ireland.|UCD Academic Centre on Rare Diseases, School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland.|Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland.
authors.forename: Sally Ann
authors.initials: SA
authors.lastname: Lynch
mesh_terms: D000328:Adult; D045744:Cell Line, Tumor; D059472:Exome / Q000235:genetics; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D008133:Long QT Syndrome / Q000235:genetics*; D008297:Male; D063209:N-Terminal Acetyltransferase A / Q000235:genetics*; D063213:N-Terminal Acetyltransferase E / Q000235:genetics*; D063206:N-Terminal Acetyltransferases / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: D063209:N-Terminal Acetyltransferase A; C504824:NAA10 protein, human; D063213:N-Terminal Acetyltransferase E; D063206:N-Terminal Acetyltransferases