Journal Article

NAA10 polyadenylation signal variants cause syndromic microphthalmia


Background. A 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. Methods. Three 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. Results. Genetic linkage analysis in family 1 supported a candidate region on Xq27-28, 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. Targetted sequencing of NAA10 in 376 additional affected individuals failed to identify variants in the PAS. Conclusion. These 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 recognized variants in PAS associated with Mendelian disorders and identified only 23 others, indicating that NAA10 harbors more than 10% of all known PAS variants. We hypothesize that PAS in other genes harbor unrecognized pathogenic variants associated with Mendelian disorders. The systematic interrogation of PAS could improve genetic testing yields.

Attached files


Johnston, Jennifer J.
Williamson, Kathleen A.
Chou, Christopher M.
Sapp, Julie C.
Ansari, Morad
Chapman, Heather M.
Cooper, David N.
Dabir, Tabib
Dudley, Jeffrey N.
Holt, Richard J.
Ragge, Nicola K.
Schäffer, Alejandro A.
Sen, Shurjo K.
Slavotinek, Anne M.
FitzPatrick, David R.
Glaser, Tom M.
Stewart, Fiona
Black, Graeme C.M.
Biesecker, Leslie G.

Oxford Brookes departments

Faculty of Health and Life Sciences


Year of publication: 2019
Date of RADAR deposit: 2019-01-30

Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License

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This RADAR resource is the Accepted Manuscript of NAA10 polyadenylation signal variants cause syndromic microphthalmia


  • Owner: Joseph Ripp
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