Investigating the Molecular Genetics of Patients with Ichthyoses/Mendelian Disorders of Cornification (MeDOC)

Leila Youssefian, Thomas Jefferson University


The ichthyoses, also known as Mendelian disorders of cornification (MeDOC), comprising a heterogeneous group of skin disorders manifesting with localized and/or generalized scaling, erythroderma, palmoplantar keratoderma, and recurrent infections are associated with considerable morbidity and occasional mortality. The Ichthyosis Consensus Conference in 2009 introduced a classification for MeDOC based on pathophysiology, clinical manifestations, and mode of inheritance. According to this classification, there are two main groups: nonsyndromic forms, with clinical findings limited to the skin, and syndromic types, with the involvement of additional organ systems. The inheritance in different families can be either autosomal dominant, autosomal recessive or X-linked dominant or recessive. Currently, at least 67 distinct genes have been associated with different forms of ichthyosis, and mutations result in defective skin barrier function. These genes can be categorized based on their physiological involvement, including genes encoding structural components of the epidermis, those involved in epidermal lipid metabolism, or those critical for cell-cell adhesion and keratinocyte differentiation. This study focused on a cohort of 179 consanguineous families (comprising 138 non-syndromic, 29 syndromic,12 other unknown cases). We performed a systematic, step-wise process of sequencing by a gene-targeted array facilitated by homozygosity mapping and RNA-Seq. The unresolved cases were then subjected to whole-exome and whole-genome sequencing techniques to identify novel candidate genes and mutant alleles in this group of disorders. Purpose of this study was to test the hypothesis that such mutations reside in previously unreported genes or in known genes but in the areas not captured by the current sequencing technologies. The identification of the new candidate genes was facilitated in consanguineous families by homozygosity mapping using a high-density genome-wide single nucleotide polymorphism-based array. The utilization of RNA-seq also allowed us to profile the transcriptome for the consequences of variants of unknown significance (VUS) on the splicing process, providing information on altered gene expression, potentially identifying regulatory mutations altering the level of expression or the stability of the mRNA transcripts. For those cases in which no pathogenic mutations were found by a combination of the sequencing with the ichthyosis-associated targeted panel and homozygosity mapping, we applied whole-exome sequencing (WES) and whole-genome sequencing (WGS), followed by appropriate bioinformatics analysis. Also, consequences of the novel mutations in a subset of patients, such as cases with SDR9C7 mutations, were examined by the development of organotypic 3D skin equivalent constructs, and functional validation was assessed by this skin constructs through siRNA systems, followed by morphologic examination and assessment of perturbations in the barrier function of the epidermis. Collectively, we identified novel mutant alleles in genes previously not recognized as pathogenic for keratinization disorders. Identification of such mutations is critical for confirmation of the diagnosis with sub-classification towards phenotype/genotype correlations. Identification of specific mutations also provides tools for accurate genetic counseling and the detection of heterozygous carriers in extended families. Mutation identification also forms the basis for prenatal testing and preimplantation genetic diagnosis and will allow the application of allele-specific therapies currently being developed for this intractable group of disorders.

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Recommended Citation

Youssefian, Leila, "Investigating the Molecular Genetics of Patients with Ichthyoses/Mendelian Disorders of Cornification (MeDOC)" (2020). ETD Collection for Thomas Jefferson University. AAI27958493.