523 Disease-targeted next generation sequencing identifies mutations in consanguineous families with phenotypic spectrum of ichthyoses

Abstract

At least 38 different genes have been associated with the ichthyotic phenotypes. To ascertain the mutation landscape of ichthyosis in Iran, a country with high prevalence of consanguineous marriages, we have developed an ichthyoses-targeted next generation sequencing (NGS) array consisting of 38 genes, and we sequenced 92 patients with clinical diagnosis of either autosomal recessive congenital ichthyosis (ARCI) or a syndromic form of ichthyosis. In 63 out 92 families (69% detection rate) pathogenic variants were disclosed: 48 families were found to have mutations in 8 ARCI-associated genes: (ABCA12: 8%; ALOX12B:10%, ALOXE3:4%, CERS3:10%, CYP4F: 22%, NIPAL4: 2%, PNPLA1: 26%, TGM1: 30%). Except in one family with compound heterozygosity for ALOX12B, all ARCI families had homozygous recessive mutations. 15 families were found to have mutations in 7 genes associated with syndromic ichthyosis: Chanarin-Dorfman (ABHD5 mutations, 3 families), Sjogren-Larsson (ALDH3A2 mutation, 1 family), neonatal ichthyosis and sclerosing cholangitis (NISCH) (CLDN1 mutation, 1 family), chondrodysplasia punctata, X-linked dominant (EBP mutation, 1 family), Keratitis-ichthyosis-deafness (KID) (GJB2 mutations, 2 families), Netherton (SPINK5 mutations, 5 families), ichthyosis with hypotrichosis (ST14 mutation, 1 family), and Ichthyosis, X-linked (STS mutation, 1 family). These studies reveal a difference in the mutation landscape in poorly-researched, low-resource countries and well-characterized Western populations. Also, it shows that extremely rare alleles are more prevalent in gene pool of populations with consanguinity and emphasizes the importance of genetic studies of these populations for better understanding of ichthyosis pathogenesis.