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Extending the PAX1 spectrum: a dominantly inherited variant causes oculo-auriculo-vertebral syndrome

Oculo-auriculo-vertebral syndrome (OAVS) is a clinically heterogeneous disorder, with both genetic and environmental contributors. Multiple genes have been associated with OAVS and common molecular pathways, such as retinoic acid and the PAX-SIX-EYA-DACH (PSED) network, are being implicated in the d...

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Autores principales: Carter, Shannon, Fellows, Bridget J., Gibson, Kate, Bicknell, Louise S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9553880/
https://www.ncbi.nlm.nih.gov/pubmed/35879406
http://dx.doi.org/10.1038/s41431-022-01154-2
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author Carter, Shannon
Fellows, Bridget J.
Gibson, Kate
Bicknell, Louise S.
author_facet Carter, Shannon
Fellows, Bridget J.
Gibson, Kate
Bicknell, Louise S.
author_sort Carter, Shannon
collection PubMed
description Oculo-auriculo-vertebral syndrome (OAVS) is a clinically heterogeneous disorder, with both genetic and environmental contributors. Multiple genes have been associated with OAVS and common molecular pathways, such as retinoic acid and the PAX-SIX-EYA-DACH (PSED) network, are being implicated in the disease pathophysiology. Biallelic homozygous nonsense or hypomorphic missense mutations in PAX1 cause otofaciocervical syndrome type 2 (OTFCS2), a similar but more severe multi-system disorder that can be accompanied by severe combined immunodeficiency due to thymic aplasia. Here we have identified a multi-generational family with mild features of OAVS segregating a heterozygous frameshift in PAX1. The four base duplication is expected to result in nonsense-mediated decay, and therefore cause a null allele. While there was full penetrance of the variant, expressivity of facial and ear features were variable. Our findings indicate there can be monoallelic and biallelic disorders associated with PAX1, and further implicate the PSED network in OAVS.
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spelling pubmed-95538802022-10-13 Extending the PAX1 spectrum: a dominantly inherited variant causes oculo-auriculo-vertebral syndrome Carter, Shannon Fellows, Bridget J. Gibson, Kate Bicknell, Louise S. Eur J Hum Genet Brief Communication Oculo-auriculo-vertebral syndrome (OAVS) is a clinically heterogeneous disorder, with both genetic and environmental contributors. Multiple genes have been associated with OAVS and common molecular pathways, such as retinoic acid and the PAX-SIX-EYA-DACH (PSED) network, are being implicated in the disease pathophysiology. Biallelic homozygous nonsense or hypomorphic missense mutations in PAX1 cause otofaciocervical syndrome type 2 (OTFCS2), a similar but more severe multi-system disorder that can be accompanied by severe combined immunodeficiency due to thymic aplasia. Here we have identified a multi-generational family with mild features of OAVS segregating a heterozygous frameshift in PAX1. The four base duplication is expected to result in nonsense-mediated decay, and therefore cause a null allele. While there was full penetrance of the variant, expressivity of facial and ear features were variable. Our findings indicate there can be monoallelic and biallelic disorders associated with PAX1, and further implicate the PSED network in OAVS. Springer International Publishing 2022-07-25 2022-10 /pmc/articles/PMC9553880/ /pubmed/35879406 http://dx.doi.org/10.1038/s41431-022-01154-2 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Brief Communication
Carter, Shannon
Fellows, Bridget J.
Gibson, Kate
Bicknell, Louise S.
Extending the PAX1 spectrum: a dominantly inherited variant causes oculo-auriculo-vertebral syndrome
title Extending the PAX1 spectrum: a dominantly inherited variant causes oculo-auriculo-vertebral syndrome
title_full Extending the PAX1 spectrum: a dominantly inherited variant causes oculo-auriculo-vertebral syndrome
title_fullStr Extending the PAX1 spectrum: a dominantly inherited variant causes oculo-auriculo-vertebral syndrome
title_full_unstemmed Extending the PAX1 spectrum: a dominantly inherited variant causes oculo-auriculo-vertebral syndrome
title_short Extending the PAX1 spectrum: a dominantly inherited variant causes oculo-auriculo-vertebral syndrome
title_sort extending the pax1 spectrum: a dominantly inherited variant causes oculo-auriculo-vertebral syndrome
topic Brief Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9553880/
https://www.ncbi.nlm.nih.gov/pubmed/35879406
http://dx.doi.org/10.1038/s41431-022-01154-2
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