A novel autosomal recessiveGJB2-associated disorder: Ichthyosis follicularis, bilateral severe sensorineural hearing loss, and punctate palmoplantar keratoderma

Abstract

Ichthyosis follicularis, a distinct cutaneous entity reported in combination with atrichia, and photophobia has been associated with mutations in MBTPS2. We sought the genetic cause of a novel syndrome of ichthyosis follicularis, bilateral severe sensorineural hearing loss and punctate palmoplantar keratoderma in two families. We performed whole exome sequencing on three patients from two families. The pathogenicity and consequences of mutations were studied in the Xenopus oocyte expression system and by molecular modeling analysis. Compound heterozygous mutations in the GJB2 gene were discovered: a pathogenic c.526A>G; p.Asn176Asp, and a common frameshift mutation, c.35delG; p.Gly12Valfs*2. The p.Asn176Asp missense mutation was demonstrated to significantly reduce the cell–cell gap junction channel activity and increase the nonjunctional hemichannel activity in the Xenopus oocyte expression system. Molecular modeling analyses of the mutant Cx26 protein revealed significant changes in the structural characteristics and electrostatic potential of the Cx26, either in hemichannel or gap junction conformation. Thus, association of a new syndrome of an autosomal recessive disorder of ichthyosis follicularis, bilateral severe sensorineural hearing loss and punctate palmoplantar keratoderma with mutations in GJB2, expands the phenotypic spectrum of the GJB2‐associated disorders. The findings attest to the complexity of the clinical consequences of different mutations in GJB2.

Autosomal recessive congenital ichthyosis: Genomic landscape and phenotypic spectrum in a cohort of 125 consanguineous families

“…On this basis, ichthyosis has been divided into two broad categories, viz., the nonsyndromic and syndromic forms. In the syndromic forms, ichthyosis is one of the manifestations of a single gene multisystem disorder (Youssefian, Vahidnezhad, et al., ). The inherited forms of ichthyosis are usually present at birth, but the subsequent evolution of the disease and the final outcome can be highly variable.…”

Comprehensive simulation and interpretation of single nucleotide substitutions in GJB2 reveals the genetic and phenotypic landscape of GJB2-related hearing loss

“…It is worth noting that although syndromic phenotypes are generally inherited in an autosomal dominant manner in the GJB2 gene, two variants (I82V and N176D) causing syndromic phenotypes were reported to segregate recessively. 28; 29 These results shed light on the phenotypic heterogenicity of Cx26, and the distribution of disease-causing missense variants within GJB2 .…”

Arrhythmogenic right ventricular cardiomyopathy in patients with biallelic JUP-associated skin fragility

“…For targeted NGS, DNA was isolated from peripheral blood samples taken from the patients, their parents, and other clinically affected and unaffected family members. For details of the library construction, data capturing and bioinformatics, see the references 23 , 25 . The second mutation detection approach utilized RNA-based NGS via RNA-Seq analysis of a whole skin biopsy from Patient 2 as well as six unrelated healthy controls.…”

“…Indel variants were filtered for exonic in-frame insertions and deletions, frameshift mutations, and gained/lost start or stop codon. Additionally, only variants with total frequencies of < 0.001 or those without frequency data available in Genomes, gnomAD and ExAC databases were examined 23 .…”