NAA10 polyadenylation signal variants cause syndromic microphthalmia

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 C.M. Black, Leslie G. Biesecker

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
JournalJournal of medical genetics
DOIs
StatePublished - Jan 1 2019

Fingerprint

Microphthalmos
Polyadenylation
Exome
Anophthalmos
Genes
Polymerase Chain Reaction
Acetyltransferases
Genetic Linkage
Genetic Testing
3' Untranslated Regions
RNA
Messenger RNA

Keywords

  • Naa10
  • polyadenylation signal

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Johnston, J. J., Williamson, K. A., Chou, C. M., Sapp, J. C., Ansari, M., Chapman, H. M., ... Biesecker, L. G. (2019). NAA10 polyadenylation signal variants cause syndromic microphthalmia. Journal of medical genetics. https://doi.org/10.1136/jmedgenet-2018-105836

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 C.M.; Biesecker, Leslie G.

In: Journal of medical genetics, 01.01.2019.

Research output: Contribution to journalArticle

Johnston, JJ, Williamson, KA, Chou, CM, Sapp, JC, Ansari, M, Chapman, HM, Cooper, DN, Dabir, T, Dudley, JN, Holt, RJ, Ragge, NK, Schäffer, AA, Sen, SK, Slavotinek, AM, Fitzpatrick, DR, Glaser, TM, Stewart, F, Black, GCM & Biesecker, LG 2019, 'NAA10 polyadenylation signal variants cause syndromic microphthalmia', Journal of medical genetics. https://doi.org/10.1136/jmedgenet-2018-105836
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 C.M. ; Biesecker, Leslie G. / NAA10 polyadenylation signal variants cause syndromic microphthalmia. In: Journal of medical genetics. 2019.
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AU - Johnston, Jennifer J.

AU - Williamson, Kathleen A.

AU - Chou, Christopher M.

AU - Sapp, Julie C.

AU - Ansari, Morad

AU - Chapman, Heather M.

AU - Cooper, David N.

AU - Dabir, Tabib

AU - Dudley, Jeffrey N.

AU - Holt, Richard J.

AU - Ragge, Nicola K.

AU - Schäffer, Alejandro A.

AU - Sen, Shurjo K.

AU - Slavotinek, Anne M.

AU - Fitzpatrick, David R.

AU - Glaser, Thomas M

AU - Stewart, Fiona

AU - Black, Graeme C.M.

AU - Biesecker, Leslie G.

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N2 - 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.

AB - 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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