NAA10 polyadenylation signal variants cause syndromic microphthalmia

Abstract

BackgroundA single variant in NAA10 (c.471+2T>A), the gene encoding N-acetyltransferase 10, has been associated with Lenz microphthalmia syndrome. In this study, we aimed to identify causative variants in families with syndromic X-linked microphthalmia.MethodsThree families, including 15 affected individuals with syndromic X-linked microphthalmia, underwent analyses including linkage analysis, exome sequencing and targeted gene sequencing. The consequences of two identified variants in NAA10 were evaluated using quantitative PCR and RNAseq.ResultsGenetic linkage analysis in family 1 supported a candidate region on Xq27-q28, which included NAA10. Exome sequencing identified a hemizygous NAA10 polyadenylation signal (PAS) variant, chrX:153,195,397T>C, c.*43A>G, which segregated with the disease. Targeted sequencing of affected males from families 2 and 3 identified distinct NAA10 PAS variants, chrX:g.153,195,401T>C, c.*39A>G and chrX:g.153,195,400T>C, c.*40A>G. All three variants were absent from gnomAD. Quantitative PCR and RNAseq showed reduced NAA10 mRNA levels and abnormal 3′ UTRs in affected individuals. Targeted sequencing of NAA10 in 376 additional affected individuals failed to identify variants in the PAS.ConclusionThese data show that PAS variants are the most common variant type in NAA10-associated syndromic microphthalmia, suggesting reduced RNA is the molecular mechanism by which these alterations cause microphthalmia/anophthalmia. We reviewed recognised variants in PAS associated with Mendelian disorders and identified only 23 others, indicating that NAA10 harbours more than 10% of all known PAS variants. We hypothesise that PAS in other genes harbour unrecognised pathogenic variants associated with Mendelian disorders. The systematic interrogation of PAS could improve genetic testing yields.

A Japanese boy with NAA10-related syndrome and hypertrophic cardiomyopathy

“…The frequently observed symptoms are as follows: Ree et al 10 Popp et al 6 Esmailpour et al 5 Cheng et al 2 Slavotinek and Lee 11 , Johnston et al 7 Johnston et al 7 Johnston et al 7 The present case ID, motor developmental delay, growth failure, ophthalmic diseases, skeletal disorders, including scoliosis or digital anomalies, and cardiac disorders. Most NAA10 mutation types in male patients are missense variants, but three families, including the present case, harbor truncated mutations 2,7 . Patients with NAA10 mutations in further unstructured domains (exons 7 or 8) tend to exhibit microphthalmia or anophthalmia (Fig.…”

Variants in NAA15 cause pediatric hypertrophic cardiomyopathy

“…NAA10 has been associated with a variant of phenotypes including an X-linked disorder with developmental delay, dysmorphic features and lethal cardiac arrhythmias, Lenz microphthalmia syndrome, Ogden syndrome, and neurodevelopmental disorders (Casey et al, 2015;Esmailpour et al, 2014;Johnston et al, 2019;Myklebust et al, 2015;Popp et al, 2015;Ree et al, 2019;Rope et al, 2011;Sauiner et al, 2016;Sidhu et al, 2017). The largest report of patients with NAA10-reated syndrome, as published by Cheng et al in 2020, included 23 individuals from 23 families.…”

Emerging Roles of RNA 3′-end Cleavage and Polyadenylation in Pathogenesis, Diagnosis and Therapy of Human Disorders

“…This is particularly evident in genes in which the proximal PAS contains a canonical hexamer. For example, in patients suffering syndromic microphthalmia, various mutations in the proximal canonical PAS of the N-alpha-acetyltransferase 10, NatA catalytic subunit (NAA10) gene result in isoform lengthening from increased use of a distal rare AAATAA PAS, leading to decreases in mRNA expression of approximately 50% [175]. Similarly, in systemic lupus erythematosus (SLE), a SNP (rs6598) in the proximal canonical PAS of GTPase, IMAP family member 5 (GIMAP5) produces the rare AATAGA hexamer.…”