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NAA10 polyadenylation signal variants cause syndromic microphthalmia.
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, Thomas M; Stewart, Fiona; Black, Graeme Cm; Biesecker, Leslie G.
Afiliação
  • Johnston JJ; National Institutes of Health, National Human Genome Research Institute, Bethesda, Maryland, USA.
  • Williamson KA; MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, UK.
  • Chou CM; Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, USA.
  • Sapp JC; Department of Emergency Medicine, The Permanente Medical Group (TPMG), Roseville/Sacramento, California, USA.
  • Ansari M; National Institutes of Health, National Human Genome Research Institute, Bethesda, Maryland, USA.
  • Chapman HM; MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
  • Cooper DN; DNA Diagnostic Laboratory, South East Scotland Regional Genetics Services, Western General Hospital, Edinburgh, UK.
  • Dabir T; Department of Cell Biology and Human Anatomy, University of California Davis, Davis, California, USA.
  • Dudley JN; Institute of Medical Genetics, Cardiff University, Cardiff, UK.
  • Holt RJ; Northern Ireland Regional Genetics Service (NIRGS), Belfast City Hospital, Belfast, UK.
  • Ragge NK; National Institutes of Health, National Human Genome Research Institute, Bethesda, Maryland, USA.
  • Schäffer AA; Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, UK.
  • Sen SK; Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, UK.
  • Slavotinek AM; West Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK.
  • FitzPatrick DR; Computational Biology Branch, National Center for Biotechnology Information, Bethesda, Maryland, USA.
  • Glaser TM; Cancer Data Science Laboratory, National Cancer Institute, Bethesda, Maryland, USA.
  • Stewart F; Leidos Biomedical Research, Inc, Basic Science Program, Cancer & Inflammation, Frederick National Laboratory for Cancer Research, Bethesda, Maryland, USA.
  • Black GC; Department of Pediatrics and Institute for Human Genetics, University of California San Francisco, San Francisco, California, USA.
  • Biesecker LG; MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, UK.
J Med Genet ; 56(7): 444-452, 2019 07.
Article em En | MEDLINE | ID: mdl-30842225
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Poli A / Variação Genética / Predisposição Genética para Doença / Regiões 3' não Traduzidas / Estudos de Associação Genética / Acetiltransferase N-Terminal A / Acetiltransferase N-Terminal E Tipo de estudo: Prognostic_studies Limite: Female / Humans / Male Idioma: En Ano de publicação: 2019 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Poli A / Variação Genética / Predisposição Genética para Doença / Regiões 3' não Traduzidas / Estudos de Associação Genética / Acetiltransferase N-Terminal A / Acetiltransferase N-Terminal E Tipo de estudo: Prognostic_studies Limite: Female / Humans / Male Idioma: En Ano de publicação: 2019 Tipo de documento: Article