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Non-Penetrance for Ocular Phenotype in Two Individuals Carrying Heterozygous Loss-of-Function ZEB1 Alleles
L. Dudakova, V. Stranecky, L. Piherova, T. Palecek, N. Pontikos, S. Kmoch, P. Skalicka, M. Vaneckova, AE. Davidson, P. Liskova
Language English Country Switzerland
Document type Case Reports, Journal Article, Research Support, Non-U.S. Gov't
NLK
Free Medical Journals
from 2010
PubMed Central
from 2010
Europe PubMed Central
from 2010
ProQuest Central
from 2010-03-01
Open Access Digital Library
from 2010-01-01
Open Access Digital Library
from 2010-01-01
ROAD: Directory of Open Access Scholarly Resources
from 2010
PubMed
33946386
DOI
10.3390/genes12050677
Knihovny.cz E-resources
- MeSH
- Corneal Dystrophies, Hereditary genetics pathology MeSH
- Haploinsufficiency MeSH
- Heterozygote MeSH
- Cells, Cultured MeSH
- Middle Aged MeSH
- Humans MeSH
- Loss of Function Mutation * MeSH
- Penetrance * MeSH
- Pedigree MeSH
- Zinc Finger E-box-Binding Homeobox 1 genetics metabolism MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Publication type
- Journal Article MeSH
- Case Reports MeSH
- Research Support, Non-U.S. Gov't MeSH
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.
References provided by Crossref.org
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- $a 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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