Clinical variability of the GJB4:c.35G > A gene variant: a study of a large Brazilian erythrokeratodermia pedigree

• Published in: International journal of dermatology Vol. 59; no. 6; pp. 722 - 725
• Main Authors: Oliveira, Renan Tironi G., Christofolini, Denise Maria, Criado, Paulo R., Lacaz Martins, Eduardo, Kelsell, David, Machado Filho, Carlos D’Apparecida Santos
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.06.2020
• Subjects: Brazil; Codification; Connexin 43; Connexins; Connexins - genetics; Deoxyribonucleic acid; DNA; DNA Mutational Analysis; DNA sequencing; Erythrokeratodermia Variabilis - genetics; Erythrokeratodermia Variabilis - pathology; Female; Gap junctions; Genes; Genetic Heterogeneity; Genetic screening; Heterogeneity; Heterozygote; Humans; Keratinization; Male; Nails (Anatomy); Pedigree; Phenotypes; Plaques; Polymorphism, Single Nucleotide; Skin - pathology; Brazil
• ISSN: 0011-9059; 1365-4632
• DOI: 10.1111/ijd.14894

Background Erythrokeratodermas are a heterogeneous group of keratinization disorders. They are inherited in both autosomal dominant and autosomal recessive pattern. Erythrokeratoderma variabilis et progressive (EKVP) is a disorder caused by variations in genes that codify connexins (GJA1, GJB3, GJB4). The distinction between different phenotypes is not always simple. Age of presentation varies from birth to adulthood; stationary or migratory erythematous plaques associated with nonmigratory hyperkeratosis are characteristic of this disorder. Nails, hair, and teeth are not affected. Methods In order to describe the clinical phenotypes and molecular findings in a large Brazilian pedigree affected by erythrokeratoderma, we performed a clinical evaluation of four patients with different presentations of erythrokeratoderma from the same family, in which there are 35 affected members distributed in six generations. Genomic DNA evaluation by Sanger sequencing of GJB3 and GJB4 was performed in two affected family members with different phenotypes. Results Clinical heterogeneity in affected patients was remarkable. In patients investigated with genetic testing, a heterozygous pathogenic gene variant in the GJB4 (gap junction protein beta‐4) gene was found positive for GJB4:c.35G>A (rsrs80358211). One patient also presented a synonymous variant in GJB3:c.357C>T (rs41310442). Conclusion Variants in GJB4 are classically associated with Erythrokeratodermia variabilis, but there is remarkable clinical heterogeneity. Our observation that the same variant caused different phenotypes within the same family corroborates clinical heterogeneity and suggests that other genes that compose the genetic background exert some influence on the disease phenotype.