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Non-Penetrance for Ocular Phenotype in Two Individuals Carrying Heterozygous Loss-of-Function ZEB1 Alleles

ZEB1 loss-of-function (LoF) alleles are known to cause a rare autosomal dominant disorder—posterior polymorphous corneal dystrophy type 3 (PPCD3). To date, 50 pathogenic LoF variants have been identified as disease-causing and familial studies have indicated that the PPCD3 phenotype is penetrant in...

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Autores principales: Dudakova, Lubica, Stranecky, Viktor, Piherova, Lenka, Palecek, Tomas, Pontikos, Nikolas, Kmoch, Stanislav, Skalicka, Pavlina, Vaneckova, Manuela, Davidson, Alice E., Liskova, Petra
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146820/
https://www.ncbi.nlm.nih.gov/pubmed/33946386
http://dx.doi.org/10.3390/genes12050677
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author Dudakova, Lubica
Stranecky, Viktor
Piherova, Lenka
Palecek, Tomas
Pontikos, Nikolas
Kmoch, Stanislav
Skalicka, Pavlina
Vaneckova, Manuela
Davidson, Alice E.
Liskova, Petra
author_facet Dudakova, Lubica
Stranecky, Viktor
Piherova, Lenka
Palecek, Tomas
Pontikos, Nikolas
Kmoch, Stanislav
Skalicka, Pavlina
Vaneckova, Manuela
Davidson, Alice E.
Liskova, Petra
author_sort Dudakova, Lubica
collection PubMed
description ZEB1 loss-of-function (LoF) alleles are known to cause a rare autosomal dominant disorder—posterior polymorphous corneal dystrophy type 3 (PPCD3). To date, 50 pathogenic LoF variants have been identified as disease-causing and familial studies have indicated that the PPCD3 phenotype is penetrant in approximately 95% of carriers. In this study, we interrogated in-house exomes (n = 3616) and genomes (n = 88) for the presence of putative heterozygous LoF variants in ZEB1. Next, we performed detailed phenotyping in a father and his son who carried a novel LoF c.1279C>T; p.(Glu427*) variant in ZEB1 (NM_030751.6) absent from the gnomAD v.2.1.1 dataset. Ocular examination of the two subjects did not show any abnormalities characteristic of PPCD3. GnomAD (n = 141,456 subjects) was also interrogated for LoF ZEB1 variants, notably 8 distinct heterozygous changes presumed to lead to ZEB1 haploinsufficiency, not reported to be associated with PPCD3, have been identified. The NM_030751.6 transcript has a pLI score ≥ 0.99, indicating extreme intolerance to haploinsufficiency. In conclusion, ZEB1 LoF variants are present in a general population at an extremely low frequency. As PPCD3 can be asymptomatic, the true penetrance of ZEB1 LoF variants remains currently unknown but is likely to be lower than estimated by the familial led approaches adopted to date.
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spelling pubmed-81468202021-05-26 Non-Penetrance for Ocular Phenotype in Two Individuals Carrying Heterozygous Loss-of-Function ZEB1 Alleles Dudakova, Lubica Stranecky, Viktor Piherova, Lenka Palecek, Tomas Pontikos, Nikolas Kmoch, Stanislav Skalicka, Pavlina Vaneckova, Manuela Davidson, Alice E. Liskova, Petra Genes (Basel) Article ZEB1 loss-of-function (LoF) alleles are known to cause a rare autosomal dominant disorder—posterior polymorphous corneal dystrophy type 3 (PPCD3). To date, 50 pathogenic LoF variants have been identified as disease-causing and familial studies have indicated that the PPCD3 phenotype is penetrant in approximately 95% of carriers. In this study, we interrogated in-house exomes (n = 3616) and genomes (n = 88) for the presence of putative heterozygous LoF variants in ZEB1. Next, we performed detailed phenotyping in a father and his son who carried a novel LoF c.1279C>T; p.(Glu427*) variant in ZEB1 (NM_030751.6) absent from the gnomAD v.2.1.1 dataset. Ocular examination of the two subjects did not show any abnormalities characteristic of PPCD3. GnomAD (n = 141,456 subjects) was also interrogated for LoF ZEB1 variants, notably 8 distinct heterozygous changes presumed to lead to ZEB1 haploinsufficiency, not reported to be associated with PPCD3, have been identified. The NM_030751.6 transcript has a pLI score ≥ 0.99, indicating extreme intolerance to haploinsufficiency. In conclusion, ZEB1 LoF variants are present in a general population at an extremely low frequency. As PPCD3 can be asymptomatic, the true penetrance of ZEB1 LoF variants remains currently unknown but is likely to be lower than estimated by the familial led approaches adopted to date. MDPI 2021-04-30 /pmc/articles/PMC8146820/ /pubmed/33946386 http://dx.doi.org/10.3390/genes12050677 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Dudakova, Lubica
Stranecky, Viktor
Piherova, Lenka
Palecek, Tomas
Pontikos, Nikolas
Kmoch, Stanislav
Skalicka, Pavlina
Vaneckova, Manuela
Davidson, Alice E.
Liskova, Petra
Non-Penetrance for Ocular Phenotype in Two Individuals Carrying Heterozygous Loss-of-Function ZEB1 Alleles
title Non-Penetrance for Ocular Phenotype in Two Individuals Carrying Heterozygous Loss-of-Function ZEB1 Alleles
title_full Non-Penetrance for Ocular Phenotype in Two Individuals Carrying Heterozygous Loss-of-Function ZEB1 Alleles
title_fullStr Non-Penetrance for Ocular Phenotype in Two Individuals Carrying Heterozygous Loss-of-Function ZEB1 Alleles
title_full_unstemmed Non-Penetrance for Ocular Phenotype in Two Individuals Carrying Heterozygous Loss-of-Function ZEB1 Alleles
title_short Non-Penetrance for Ocular Phenotype in Two Individuals Carrying Heterozygous Loss-of-Function ZEB1 Alleles
title_sort non-penetrance for ocular phenotype in two individuals carrying heterozygous loss-of-function zeb1 alleles
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146820/
https://www.ncbi.nlm.nih.gov/pubmed/33946386
http://dx.doi.org/10.3390/genes12050677
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