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.

Exome sequencing reveals NAA15 and PUF60 as candidate genes associated with intellectual disability

“…NAA10 is associated with Ogden syndrome, an X‐linked neurodevelopment disorder (MIM#300013). Ogden syndrome can be caused by both X‐linked dominant inheritance with a milder phenotype, or X‐linked recessive inheritance with severe phenotypes, and the syndrome is characterized by postnatal growth failure, delayed psychomotor development, ID, hypotonia, and dysmorphic features (Casey et al, ; Popp et al, ; Rope et al, ). The phenotype thus shows some shared features with the phenotype reported for patients with NAA15 DNVs.…”

The world of protein acetylation

“…Y43S (exon 3), causing an intellectual disability syndrome with facial dysmorphic features, hypotonia, scoliosis and long QT due to NAT impairment [127]. Saunier and colleagues identified three novel Naa10 mutations; the R83C mutation was detected in a male and seven girls, while the F128L mutation and F128I was detected in a girl each [128].…”

Proteomic and genomic characterization of a yeast model for Ogden syndrome

“…Since the first description of Ogden syndrome in two multiplex unrelated families, additional variants in Naa10 have been identified in other probands with non‐syndromic intellectual disabilities accompanied by postnatal growth failure and skeletal anomalies (Rauch et al, ; Popp et al, ; Saunier et al, ), one family with two brothers with syndromic intellectual disability with long QT, a prologation of the depolarization and repolarization interval of the ventricles of the heart (Casey et al, ) and one multiplex family with Lenz microphthalmia syndrome, characterized by microphthalmia or anophthalmia, developmental delay, intellectual disability, skeletal abnormalities and malformations of teeth, fingers and toes (Esmailpour et al, ). The phenotypic differences between all cases are fairly distinct, and to date there has been no unifying explanation for this, beyond just genetic background differences.…”