NAA10 polyadenylation signal variants cause syndromic microphthalmia

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

doi:10.1136/jmedgenet-2018-105836

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...

Highlights

Congenital anophthalmia and microphthalmia result from failure of early eye development
Targeted sequencing of NAA10 in 376 additional affected individuals failed to identify variants in the polyadenylation signal (PAS). 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 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

Summary

Introduction

Congenital anophthalmia and microphthalmia result from failure of early eye development. Clinical presentation in one-third of affected individuals is syndromic,[1 2] and it is genetically heterogeneous.[3] X-linked syndromic anophthalmia and microphthalmia have been shown to result from pathogenic variants in four genes: BCOR4 (MIM:300485, MCOPS2), HCCS5 (MIM:300056, MCOPS7), HMGB36 (MIM:300193, MCOPS13), and NAA107 (MIM:309800, MCOPS1). A single HGMB3 variant has been reported in one family to cause syndromic colobomatous microphthalmia.[6] Forrester et al[8] described a family segregating what they termed Lenz microphthalmia syndrome (LMS) and linkage to Xq27-q28. A c.471+2T>A splice variant in NAA10 was identified as causative, the only study to date associating NAA10 variants with syndromic microphthalmia.[7]. NAA10 (c.471+2T>A), the gene encoding N-acetyltransferase 10, has been associated with Lenz microphthalmia syndrome. We aimed to identify causative variants in families with syndromic X-linked microphthalmia

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Discussion

Conclusion