title: De novo missense mutations in the NAA10 gene cause severe non-syndromic developmental delay in males and females.
abstract: Recent studies revealed the power of whole-exome sequencing to identify mutations in sporadic cases with non-syndromic intellectual disability. We now identified de novo missense variants in NAA10 in two unrelated individuals, a boy and a girl, with severe global developmental delay but without any major dysmorphism by trio whole-exome sequencing. Both de novo variants were predicted to be deleterious, and we excluded other variants in this gene. This X-linked gene encodes N-alpha-acetyltransferase 10, the catalytic subunit of the NatA complex involved in multiple cellular processes. A single hypomorphic missense variant p.(Ser37Pro) was previously associated with Ogden syndrome in eight affected males from two different families. This rare disorder is characterized by a highly recognizable phenotype, global developmental delay and results in death during infancy. In an attempt to explain the discrepant phenotype, we used in vitro N-terminal acetylation assays which suggested that the severity of the phenotype correlates with the remaining catalytic activity. The variant in the Ogden syndrome patients exhibited a lower activity than the one seen in the boy with intellectual disability, while the variant in the girl was the most severe exhibiting only residual activity in the acetylation assays used. We propose that N-terminal acetyltransferase deficiency is clinically heterogeneous with the overall catalytic activity determining the phenotypic severity.
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Bernt
authors.initials: B
authors.lastname: Popp
authors.affiliation: 1] Department of Molecular Biology, University of Bergen, Bergen, Norway [2] Department of Surgery, Haukeland University Hospital, Bergen, Norway.
authors.forename: Svein I
authors.initials: SI
authors.lastname: Støve
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Endele
authors.affiliation: Department of Molecular Biology, University of Bergen, Bergen, Norway.
authors.forename: Line M
authors.initials: LM
authors.lastname: Myklebust
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Hoyer
authors.affiliation: Institute of Biochemistry, Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Sticht
authors.affiliation: Institute of Medical Genetics, University of Zurich, Schlieren, Switzerland.
authors.forename: Silvia
authors.initials: S
authors.lastname: Azzarello-Burri
authors.affiliation: Institute of Medical Genetics, University of Zurich, Schlieren, Switzerland.
authors.forename: Anita
authors.initials: A
authors.lastname: Rauch
authors.affiliation: 1] Department of Molecular Biology, University of Bergen, Bergen, Norway [2] Department of Surgery, Haukeland University Hospital, Bergen, Norway.
authors.forename: Thomas
authors.initials: T
authors.lastname: Arnesen
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Reis
mesh_terms: D000595:Amino Acid Sequence; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D002658:Developmental Disabilities / Q000175:diagnosis / Q000235:genetics*; D005091:Exons; D019066:Facies; D005260:Female; D056726:Genetic Association Studies; D056426:Genetic Loci; D006801:Humans; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D063209:N-Terminal Acetyltransferase A / Q000737:chemistry / Q000235:genetics*; D063213:N-Terminal Acetyltransferase E / Q000737:chemistry / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011487:Protein Conformation; D016415:Sequence Alignment
chemical_list: D063209:N-Terminal Acetyltransferase A; C504824:NAA10 protein, human; D063213:N-Terminal Acetyltransferase E
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