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NAA10 polyadenylation signal variants cause syndromic microphthalmia
  1. Jennifer J Johnston1,
  2. Kathleen A Williamson2,
  3. Christopher M Chou3,4,
  4. Julie C Sapp1,
  5. Morad Ansari5,6,
  6. Heather M Chapman7,
  7. David N Cooper8,
  8. Tabib Dabir9,
  9. Jeffrey N Dudley1,
  10. Richard J Holt10,
  11. Nicola K Ragge10,11,
  12. Alejandro A Schäffer12,13,
  13. Shurjo K Sen14,
  14. Anne M Slavotinek15,
  15. David R FitzPatrick2,
  16. Thomas M Glaser7,
  17. Fiona Stewart9,
  18. Graeme CM Black16,17,
  19. Leslie G Biesecker1
  1. 1 National Institutes of Health, National Human Genome Research Institute, Bethesda, Maryland, USA
  2. 2 MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, UK
  3. 3 Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, USA
  4. 4 Department of Emergency Medicine, The Permanente Medical Group (TPMG), Roseville/Sacramento, California, USA
  5. 5 MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
  6. 6 DNA Diagnostic Laboratory, South East Scotland Regional Genetics Services, Western General Hospital, Edinburgh, UK
  7. 7 Department of Cell Biology and Human Anatomy, University of California Davis, Davis, California, USA
  8. 8 Institute of Medical Genetics, Cardiff University, Cardiff, UK
  9. 9 Northern Ireland Regional Genetics Service (NIRGS), Belfast City Hospital, Belfast, UK
  10. 10 Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, UK
  11. 11 West Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, UK
  12. 12 Computational Biology Branch, National Center for Biotechnology Information, Bethesda, Maryland, USA
  13. 13 Cancer Data Science Laboratory, National Cancer Institute, Bethesda, Maryland, USA
  14. 14 Leidos Biomedical Research, Inc, Basic Science Program, Cancer & Inflammation, Frederick National Laboratory for Cancer Research, Bethesda, Maryland, USA
  15. 15 Department of Pediatrics and Institute for Human Genetics, University of California San Francisco, San Francisco, California, USA
  16. 16 Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
  17. 17 St Mary’s Hospital, Manchester Centre for Genomic Medicine, Manchester Academic Health Sciences Centre, Manchester University NHS Foundation Trust, Manchester, UK
  1. Correspondence to Dr Jennifer J Johnston, Genetic Disease Research Branch, National Human Genome Research Institute, Bethesda, Maryland 20892, USA; jjohnsto{at}


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-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.

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 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.

  • Naa10
  • polyadenylation signal

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  • Contributors All authors fulfil the criteria for authorship. AAS performed and interpreted linkage analysis of family 1. JJJ performed haplotype analysis, interpreted NGS data and performed Sanger confirmation in family 1. JCS, FS and LGB provided clinical management for family 1. HMC performed sequence analysis of NAA10 in family 2. CMC and AMS provided clinical management for family 2. JND performed and interpreted qPCR experiments in families 1 and 2. SKS analysed RNA-seq data for families 1 and 2. KW and MA interpreted NGS data in family 3 and analysed sequence data in a cohort of individuals with anophthalmia/microphthalmia for variants in NAA10. TD provided clinical management for family 3. RJH and NR performed and analysed sequencing of NAA10 in a cohort of individuals with anophthalmia/microphthalmia/coloboma. DNC provided an analysis of polyadenylation signal variants within the Human Gene Mutation Database. JJJ and LGB drafted the manuscript, and all authors contributed to the manuscript. All authors read and approved the final manuscript. LGB (family 1), GCB (family 1), TMG (family 2) and DRF (family 3) planned the study. JJJ submitted the study.

  • Funding This work was supported by funding from the Intramural Research Program of the National Human Genome Research Institute (LGB, JJJ and JCS: grants HG200328 11 and HG200388 03). This work was supported in part by funding from the Intramural Research Program of the National Library of Medicine (AAS: grant LM00097), the extramural research programme of the National Human Genome Research Institute (AMS: grant 5U01HG009599 02), the National Institutes of Health (TMG and HMC: grant EY19497), the Hartwell Foundation (HMC), the MRC University Unit award to the University of Edinburgh for the MRC Human Genetics Unit (DRF and KW), and the MRC IGMM Translational Science Initiative (MA). This work was supported in part by grants from Baillie Gifford, Visually Impaired Children Taking Action ( and Microphthalmia, Anophthalmia, Coloboma Support (

  • Competing interests LGB receives royalties from Genentech Corp, is an advisor to the Illumina Corp, received honoraria from Wiley-Blackwell and receives honoraria from Cold Spring Harbor Press. DNC is in receipt of funding from Qiagen Inc through a License Agreement with Cardiff University. AMS receives honoraria from Wiley-Blackwell, Inc, Oxford University Press and UptoDate, Inc.

  • Ethics approval This study was approved by Institutional Review Boards at the National Institutes of Health (NIH), the UK Multicentre Research Ethics Committee, the University of Michigan, the University of California, Davis and the Huntingdon Ethics Committee, UK.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Patient consent for publication Not required.

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