Year: 2019
Type: article
Study design: Observational Study
Abstract: 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.
Source: Journal of Medical Genetics
Authors: Jennifer J Johnston, Kathleen A Williamson, Christopher M Chou, Julie C Sapp, Morad Ansari, Heather M Chapman, David N Cooper, Tabib Dabir, Jeffrey N Dudley, Richard J Holt, Nicola K Ragge, Alejandro A Schäffer, Shurjo K Sen, Anne M Slavotinek, David R FitzPatrick, Thomas M Glaser, Fiona Stewart, Graeme CM Black, Leslie G Biesecker
Institutions: National Institutes of Health, National Human Genome Research Institute, Institute of Genetics and Cancer, MRC Human Genetics Unit, University of Edinburgh, University of Michigan, Michigan Medicine, Kaiser Permanente Roseville Medical Center, Western General Hospital, University of California, Davis, Cardiff University, Belfast City Hospital, Oxford Brookes University, Birmingham Women’s and Children’s NHS Foundation Trust, National Center for Biotechnology Information, National Cancer Institute, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc. (United States), University of California, San Francisco, Manchester Academic Health Science Centre, University of Manchester, St Mary's Hospital, Manchester University NHS Foundation Trust
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $2,378
Funders: Baillie Gifford, Hartwell Foundation, University of Oxford, Cardiff University, National Institutes of Health, Genentech, Medical Research Council, National Human Genome Research Institute, National Eye Institute, National Institute of General Medical Sciences, U.S. National Library of Medicine
Awards: Genomic sequencing to aid diagnosis in pediatric and prenatal practice: Examining clinical utility, ethical implications, payer coverage, and data integration in a diverse population., G2936945559, Michigan Predoctoral Training in Genetics, Case Studies In Genetics, Clinical and Molecular Studies of Malformations, G5644062237, Developmental Disorders: From Diagnosis to Mechanism via Cis-Regulation, G6622335928, Genetic Basis of Congenital Anophthalmia
OpenAlex ID: W2919288321