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

Author:

González-Quintana Adrián123ORCID,Garrido-Moraga Rocío3ORCID,Palencia-Pérez Sara I.4ORCID,Hernández-Martín Ángela5,Sánchez-Munárriz Jon1,Lezana-Rosales José M.67ORCID,Quesada-Espinosa Juan F.67ORCID,Martín Miguel A.2367ORCID,Arteche-López Ana67ORCID

Affiliation:

1. Servicio Bioquímica Clínica/Análisis Clínicos, Hospital 12 de Octubre, 28041 Madrid, Spain

2. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28029 Madrid, Spain

3. Grupo de Enfermedades Mitocondriales y Neurometabólicas, Instituto de Investigación Hospital 12 de Octubre (imas12), 28041 Madrid, Spain

4. Departamento de Dermatología, Hospital Universitario 12 de Octubre y Universidad Complutense de Madrid, 28041 Madrid, Spain

5. Departamento de Dermatología, Hospital Infantil Universitario Niño Jesús, 28009 Madrid, Spain

6. Servicio de Genética, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain

7. UDisGen (Unidad de Dismorfología y Genética), Hospital 12 de Octubre, 28041 Madrid, Spain

Abstract

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.

Funder

Instituto de Salud Carlos III

Ministerio de Ciencia e Innovación

Publisher

MDPI AG

Subject

Genetics (clinical),Genetics

Reference20 articles.

1. Hereditary palmoplantar keratoderma “clinical and genetic differential diagnosis”;Sakiyama;J. Dermatol.,2016

2. Master regulatory role of p63 in epidermal development and disease;Soares;Cell. Mol. Life Sci.,2018

3. Mutations in PERP Cause Dominant and Recessive Keratoderma;Duchatelet;J. Investig. Dermatol.,2019

4. Olmsted syndrome with alopecia universalis caused by heterozygous mutation in PERP;Dai;Br. J. Dermatol.,2020

5. Recurrent c.459 C>A mutation of the PERP gene results in severe Olmsted syndrome with congenital hypotrichosis, atopic dermatitis, and growth retardation;Song;J. Dermatol.,2021

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