Integration of Phenotype Term Prioritization and Gene Expression Analysis Reveals a Novel Variant in the <i>PERP</i> 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 <i>PERP</i>, a gene encoding a crucial component of desm...
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MDPI AG
2023-07-01
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| Series: | Genes |
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| Online Access: | https://www.mdpi.com/2073-4425/14/7/1494 |
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| author | Adrián González-Quintana Rocío Garrido-Moraga Sara I. Palencia-Pérez Ángela Hernández-Martín Jon Sánchez-Munárriz José M. Lezana-Rosales Juan F. Quesada-Espinosa Miguel A. Martín Ana Arteche-López |
| author_facet | Adrián González-Quintana Rocío Garrido-Moraga Sara I. Palencia-Pérez Ángela Hernández-Martín Jon Sánchez-Munárriz José M. Lezana-Rosales Juan F. Quesada-Espinosa Miguel A. Martín Ana Arteche-López |
| author_sort | Adrián González-Quintana |
| collection | DOAJ |
| 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 <i>PERP</i>, 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 <i>PERP</i> 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 <i>PERP</i> 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. |
| first_indexed | 2024-03-11T01:02:54Z |
| format | Article |
| id | doaj.art-a8864b87f554450094dae32fd4110754 |
| institution | Directory Open Access Journal |
| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-11T01:02:54Z |
| publishDate | 2023-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Genes |
| spelling | doaj.art-a8864b87f554450094dae32fd41107542023-11-18T19:31:20ZengMDPI AGGenes2073-44252023-07-01147149410.3390/genes14071494Integration of Phenotype Term Prioritization and Gene Expression Analysis Reveals a Novel Variant in the <i>PERP</i> Gene Associated with Autosomal Recessive ErythrokeratodermaAdrián González-Quintana0Rocío Garrido-Moraga1Sara I. Palencia-Pérez2Ángela Hernández-Martín3Jon Sánchez-Munárriz4José M. Lezana-Rosales5Juan F. Quesada-Espinosa6Miguel A. Martín7Ana Arteche-López8Servicio Bioquímica Clínica/Análisis Clínicos, Hospital 12 de Octubre, 28041 Madrid, SpainGrupo de Enfermedades Mitocondriales y Neurometabólicas, Instituto de Investigación Hospital 12 de Octubre (imas12), 28041 Madrid, SpainDepartamento de Dermatología, Hospital Universitario 12 de Octubre y Universidad Complutense de Madrid, 28041 Madrid, SpainDepartamento de Dermatología, Hospital Infantil Universitario Niño Jesús, 28009 Madrid, SpainServicio Bioquímica Clínica/Análisis Clínicos, Hospital 12 de Octubre, 28041 Madrid, SpainServicio de Genética, Hospital Universitario 12 de Octubre, 28041 Madrid, SpainServicio de Genética, Hospital Universitario 12 de Octubre, 28041 Madrid, SpainCentro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28029 Madrid, SpainServicio de Genética, Hospital Universitario 12 de Octubre, 28041 Madrid, SpainHereditary 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 <i>PERP</i>, 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 <i>PERP</i> 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 <i>PERP</i> 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.https://www.mdpi.com/2073-4425/14/7/1494<i>PERP</i>erythrokeratodemapalmoplantar keratodermaHPO |
| spellingShingle | Adrián González-Quintana Rocío Garrido-Moraga Sara I. Palencia-Pérez Ángela Hernández-Martín Jon Sánchez-Munárriz José M. Lezana-Rosales Juan F. Quesada-Espinosa Miguel A. Martín Ana Arteche-López Integration of Phenotype Term Prioritization and Gene Expression Analysis Reveals a Novel Variant in the <i>PERP</i> Gene Associated with Autosomal Recessive Erythrokeratoderma Genes <i>PERP</i> erythrokeratodema palmoplantar keratoderma HPO |
| title | Integration of Phenotype Term Prioritization and Gene Expression Analysis Reveals a Novel Variant in the <i>PERP</i> Gene Associated with Autosomal Recessive Erythrokeratoderma |
| title_full | Integration of Phenotype Term Prioritization and Gene Expression Analysis Reveals a Novel Variant in the <i>PERP</i> Gene Associated with Autosomal Recessive Erythrokeratoderma |
| title_fullStr | Integration of Phenotype Term Prioritization and Gene Expression Analysis Reveals a Novel Variant in the <i>PERP</i> Gene Associated with Autosomal Recessive Erythrokeratoderma |
| title_full_unstemmed | Integration of Phenotype Term Prioritization and Gene Expression Analysis Reveals a Novel Variant in the <i>PERP</i> Gene Associated with Autosomal Recessive Erythrokeratoderma |
| title_short | Integration of Phenotype Term Prioritization and Gene Expression Analysis Reveals a Novel Variant in the <i>PERP</i> Gene Associated with Autosomal Recessive Erythrokeratoderma |
| title_sort | integration of phenotype term prioritization and gene expression analysis reveals a novel variant in the i perp i gene associated with autosomal recessive erythrokeratoderma |
| topic | <i>PERP</i> erythrokeratodema palmoplantar keratoderma HPO |
| url | https://www.mdpi.com/2073-4425/14/7/1494 |
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