NAA10 mutation causing a novel intellectual disability syndrome with Long QT due to N-terminal acetyltransferase impairment.

Jillian P Casey,Marina Blenski,Francesca Brett,Joseph Galvin,Thomas Arnesen,Sally Ann Lynch,Aimee Dunne,Svein I Støve,Catherine Mcgorrian,Mary D King,Sean Ennis

doi:10.1038/srep16022

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.

Highlights

The first reported NAT gene linked to human disease was NAA10
Ogden syndrome is a rare perinatal lethal disorder characterised by global developmental delay, craniofacial abnormalities, hypotonia, cardiac arrhythmia and an aged appearance with lax skin[13]
We report on two affected brothers from a non-consanguineous Irish family presenting with an intellectual disability syndrome with facial dysmorphism, hypotonia, scoliosis and long QT (Fig. 1 and Table 1)

Summary

Introduction

The first reported NAT gene linked to human disease was NAA10. In 2011, Rope and colleagues showed that missense mutations in exon 2 of NAA10 caused Ogden syndrome[13]. De novo mutations in exons 5 and 6 were shown to cause severe non-syndromic developmental delay in an unrelated male and female child[15]. This was the first time that a female with an NAA10 mutation was shown to have a fully penetrant and severe phenotype. We report on two affected brothers from a non-consanguineous Irish family presenting with an intellectual disability syndrome with facial dysmorphism, hypotonia, scoliosis and long QT (Fig. 1 and Table 1). Their mother is mildly affected suggesting the possibility of X-linked inheritance. Functional studies showed reduced acetylation activity of the mutant Naa[10] enzyme implicating altered Nt-acetylation as one of the mechanisms contributing to the pathogenesis of syndromic intellectual disability

Methods

Results

Conclusion