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Integration of Phenotype Term Prioritization and Gene Expression Analysis Reveals a Novel Variant in the PERP Gene Associated with Autosomal Recessive Erythrokeratoderma

Hereditary palmoplantar keratodermas (PPKs) are a clinically and genetically heterogeneous group of disorders characterized by excessive epidermal thickening of palms and soles. Several genes have been associated with PPK including PERP, a gene encoding a crucial component of desmosomes that has bee...

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Autores principales: González-Quintana, Adrián, Garrido-Moraga, Rocío, Palencia-Pérez, Sara I., Hernández-Martín, Ángela, Sánchez-Munárriz, Jon, Lezana-Rosales, José M., Quesada-Espinosa, Juan F., Martín, Miguel A., Arteche-López, Ana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10379359/
https://www.ncbi.nlm.nih.gov/pubmed/37510397
http://dx.doi.org/10.3390/genes14071494
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author González-Quintana, Adrián
Garrido-Moraga, Rocío
Palencia-Pérez, Sara I.
Hernández-Martín, Ángela
Sánchez-Munárriz, Jon
Lezana-Rosales, José M.
Quesada-Espinosa, Juan F.
Martín, Miguel A.
Arteche-López, Ana
author_facet González-Quintana, Adrián
Garrido-Moraga, Rocío
Palencia-Pérez, Sara I.
Hernández-Martín, Ángela
Sánchez-Munárriz, Jon
Lezana-Rosales, José M.
Quesada-Espinosa, Juan F.
Martín, Miguel A.
Arteche-López, Ana
author_sort González-Quintana, Adrián
collection PubMed
description Hereditary palmoplantar keratodermas (PPKs) are a clinically and genetically heterogeneous group of disorders characterized by excessive epidermal thickening of palms and soles. Several genes have been associated with PPK including PERP, a gene encoding a crucial component of desmosomes that has been associated with dominant and recessive keratoderma. We report a patient with recessive erythrokeratoderma (EK) in which whole exome sequencing (WES) prioritized by human phenotype ontology (HPO) terms revealed the presence of the novel variant c.153C > A in the N-terminal region the PERP gene. This variant is predicted to have a nonsense effect, p.(Cys51Ter), resulting in a premature stop codon. We demonstrated a marked reduction in gene expression in cultured skin fibroblasts obtained from the patient. Despite the PERP gene is expressed at low levels in fibroblasts, our finding supports a loss-of-function (LoF) mechanism for the identified variant, as previously suggested in recessive EK. Our study underscores the importance of integrating HPO analysis when using WES for molecular genetic diagnosis in a clinical setting, as it facilitates continuous updates regarding gene–clinical feature associations.
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spelling pubmed-103793592023-07-29 Integration of Phenotype Term Prioritization and Gene Expression Analysis Reveals a Novel Variant in the PERP Gene Associated with Autosomal Recessive Erythrokeratoderma González-Quintana, Adrián Garrido-Moraga, Rocío Palencia-Pérez, Sara I. Hernández-Martín, Ángela Sánchez-Munárriz, Jon Lezana-Rosales, José M. Quesada-Espinosa, Juan F. Martín, Miguel A. Arteche-López, Ana Genes (Basel) Brief Report Hereditary palmoplantar keratodermas (PPKs) are a clinically and genetically heterogeneous group of disorders characterized by excessive epidermal thickening of palms and soles. Several genes have been associated with PPK including PERP, a gene encoding a crucial component of desmosomes that has been associated with dominant and recessive keratoderma. We report a patient with recessive erythrokeratoderma (EK) in which whole exome sequencing (WES) prioritized by human phenotype ontology (HPO) terms revealed the presence of the novel variant c.153C > A in the N-terminal region the PERP gene. This variant is predicted to have a nonsense effect, p.(Cys51Ter), resulting in a premature stop codon. We demonstrated a marked reduction in gene expression in cultured skin fibroblasts obtained from the patient. Despite the PERP gene is expressed at low levels in fibroblasts, our finding supports a loss-of-function (LoF) mechanism for the identified variant, as previously suggested in recessive EK. Our study underscores the importance of integrating HPO analysis when using WES for molecular genetic diagnosis in a clinical setting, as it facilitates continuous updates regarding gene–clinical feature associations. MDPI 2023-07-22 /pmc/articles/PMC10379359/ /pubmed/37510397 http://dx.doi.org/10.3390/genes14071494 Text en © 2023 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 Brief Report
González-Quintana, Adrián
Garrido-Moraga, Rocío
Palencia-Pérez, Sara I.
Hernández-Martín, Ángela
Sánchez-Munárriz, Jon
Lezana-Rosales, José M.
Quesada-Espinosa, Juan F.
Martín, Miguel A.
Arteche-López, Ana
Integration of Phenotype Term Prioritization and Gene Expression Analysis Reveals a Novel Variant in the PERP Gene Associated with Autosomal Recessive Erythrokeratoderma
title Integration of Phenotype Term Prioritization and Gene Expression Analysis Reveals a Novel Variant in the PERP Gene Associated with Autosomal Recessive Erythrokeratoderma
title_full Integration of Phenotype Term Prioritization and Gene Expression Analysis Reveals a Novel Variant in the PERP Gene Associated with Autosomal Recessive Erythrokeratoderma
title_fullStr Integration of Phenotype Term Prioritization and Gene Expression Analysis Reveals a Novel Variant in the PERP Gene Associated with Autosomal Recessive Erythrokeratoderma
title_full_unstemmed Integration of Phenotype Term Prioritization and Gene Expression Analysis Reveals a Novel Variant in the PERP Gene Associated with Autosomal Recessive Erythrokeratoderma
title_short Integration of Phenotype Term Prioritization and Gene Expression Analysis Reveals a Novel Variant in the PERP Gene Associated with Autosomal Recessive Erythrokeratoderma
title_sort integration of phenotype term prioritization and gene expression analysis reveals a novel variant in the perp gene associated with autosomal recessive erythrokeratoderma
topic Brief Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10379359/
https://www.ncbi.nlm.nih.gov/pubmed/37510397
http://dx.doi.org/10.3390/genes14071494
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