A Tunisian family with a novel mutation in the gene CYP4F22 for lamellar ichthyosis and co‐occurrence of hearing loss in a child due to mutation in the SLC26A4 gene

Abstract

Background Co‐occurrence of two genetic diseases is challenging for accurate diagnosis and genetic counseling. The recent availability of whole exome sequencing (WES) has dramatically improved the molecular diagnosis of rare genetic diseases in particular in consanguineous populations. Methods We report here on a consanguineous family from Southern Tunisia including three members affected with congenital ichthyosis. The index case had a hearing loss (HL) and ichthyosis and was primarily suspected as suffering from keratitis‐ichthyosis‐deafness (KID) syndrome. WES was performed for the index case, and all members of the nuclear family were sequenced (Sanger method). Results The WES approach allowed the identification of two strong candidate variants in two different genes; a missense mutation c.1334T>G (p.Leu445Trp) in exon 11 of SLC26A4 gene, associated with isolated HL and a novel missense mutation c.728G>T (p.Arg243Leu) in exon 8 of CYP4F22 gene likely responsible for ichthyosis. These two mutations were predicted to be pathogenic by three pathogenicity prediction softwares (Scale‐Invariant Feature Transform [SIFT], Polymorphism Phenotyping [PolyPhen], Mutation Taster) to underlie the HL and ichthyosis, respectively. Conclusions The present study raises awareness about the importance of familial history for accurate diagnosis of syndromic genetic diseases and differential diagnosis with co‐occurrence of two distinct clinical entities. In addition, in countries with limited resources, WES sequencing for a single individual provides a cost effective tool for molecular diagnosis confirmation and genetic counseling.

Spectrum of Genetic Diseases in Tunisia: Current Situation and Main Milestones Achieved

“…Another impact of the elevated rate of consanguinity and inbreeding is the cooccurrence of two or more phenotypes within the same family [42]. Comorbidity, described particularly in inbred populations, makes genetic counseling and prenatal diagnosis challenging [42,44]. The study of Romdhane and her colleagues revealed 75 genetic disease co-occurrences identified in Tunisian patients.…”

Molecular Functionality of Cytochrome P450 4 (CYP4) Genetic Polymorphisms and Their Clinical Implications

“…Ohno et al (2015) reported that CYP4F22 is responsible for the generation of acylceramide through ω-hydroxylation of long-chain fatty acids [18]. Recently, a CYP4F22 genetic variant associated with lamellar ichthyosis was reported in a Tunisian family [131]. A missense mutation in exon 8, CYP4F22 Arg243Leu, was suggested to be linked to lamellar ichthyosis and predicted to be a functionally defective variant based on in silico analysis.…”

“…Since the discovery of CYP4F22 was linked to its association with lamellar ichthyosis [18], genetic studies of CYP4F22 polymorphisms have been undertaken. A CYP4F22 variant, CYP4F22 Arg243Leu, was associated with lamellar ichthyosis in a Tunisian family [131], and further genetic studies should be conducted in clinical settings.…”

Current phenotypic and genetic spectrum of syndromic deafness in Tunisia: paving the way for precision auditory health

“…Our study showed that several SDs were originally classified as non-syndromic, which was the case for USH in the study cohort. Similarly, comorbidity cases were initially classified as SD, e.g., a co-occurrence of HI and ichthyosis that was primarily suspected as a KID syndrome in one patient ( Sayeb et al, 2019 ). Such findings imply that each isolated deafness could be considered as a SD until proven otherwise.…”