Clinical and genetic investigation of ichthyosis in familial and sporadic cases in south of Tunisia: genotype–phenotype correlation

Abstract

Background Ichthyosis is a heterogeneous group of Mendelian cornification disorders that includes syndromic and non-syndromic forms. Autosomal Recessive Congenital Ichthyosis (ARCI) and Ichthyosis Linearis Circumflexa (ILC) belong to non-syndromic forms. Syndromic ichthyosis is rather a large group of heterogeneous diseases. Overlapping phenotypes and genotypes between these disorders is a major characteristic. Therefore, determining the specific genetic background for each form would be necessary. Methods A total of 11 Tunisian patients with non-syndromic (8 with ARCI and 2 with ILC) and autosomal syndromic ichthyosis (1 patient) were screened by a custom Agilent HaloPlex multi-gene panel and the segregation of causative mutations were analyzed in available family members. Results Clinical and molecular characterization, leading to genotype–phenotype correlation in 11 Tunisian patients was carried out. Overall, we identified 8 mutations in 5 genes. Thus, in patients with ARCI, we identified a novel (c.118T > C in NIPAL4) and 4 already reported mutations (c.534A > C in NIPAL4; c.788G > A and c.1042C > T in TGM1 and c.844C > T in CYP4F22). Yellowish severe keratoderma was found to be associated with NIPAL4 variations and brachydactyly to TGM1 mutations. Two novel variations (c.5898G > C and c.2855A > G in ABCA12) seemed to be features of ILC. Delexon13 in CERS3 was reported in a patient with syndromic ichthyosis. Conclusions Our study further extends the spectrum of mutations involved in ichthyosis as well as clinical features that could help directing genetic investigation.

Whole Exome Sequencing Identifies Novel Pathogenic Variants in TGM1 and ALOX12B in Patients with Hereditary Ichthyosis

“…Ichthyosis patients can be either homozygous for a single pathogenic mutation or compound heterozygous for two different mutations (15). Besides, it has been determined that some ichthyosis clinical features are associated with particular TGM1 genotypes (10) In current study three different mutations in TGM1 were identi ed as genetic causes of ARCI in three unrelated Iranian families (Table 1), two of which (p.Lys219Glu and p.Glu266Gly) were located in highly conserved residues. p.Lys219Glu is located in β-sandwich domain, while p.Glu266Gly is located in catalytic core domain of TGM1.…”

“…Preliminary reports indicated that NGS technologies, particularly WES, represent a powerful tool for molecular diagnostics of various genodermatoses (9). An increasing number of WES-based studies have identi ed the causative variants underlying ichthyosis, suggesting WES as a diagnostic adjunct to clinical testing in these patients (10)(11)(12).…”

Erythrokeratodermia Variabilis-like Phenotype in Patients Carrying ABCA12 Mutations

“…We detected two homozygous variants each in ABCA12 : c.6852G>C, p.(Glu2284Asp), which has already been described in “patients with lamellar ichthyosis”, and the variant c.3809A>G, p.(Tyr1270Cys), which is located in transmembrane domain 1. This patient, of Tunisian origin, was born to consanguineous parents, and her case has already been published by Ennouri et al [ 21 ]. The phenotype was described there as ichthyosis linearis circumflexa.…”

Congenital Ichthyosis: Clinical and Genetic Characteristics of the Disease

“…Такие больные чаще характеризовались легкими эритематозно-сквамозными поражениями кожного покрова. Течение CIE с патогенным вариантом гена ALOX12B часто нетяжелое, что, на наш взгляд, затрудняет дифференциальную диагностику [46]. Больные с изменениями в гене ALOXE3 также имеют сходство с пациентами с дефектом ALOX12B [45].…”

“…Помимо этого, для некоторых вариантов генов TGM1 и NIPAL4 характерен эктропион, для генов TGM1 и CERS3 -брадидактилия, для гена TGM1 -аномалия развития ушей, алопеция и снижение слуха [26]. Кроме того, были выделены генотип-фенотипические ассоциации вариантов генов ALOX12B и CYP4F22 с выраженной лихенификацией и фолликулярным гиперкератозом и гена ALOXE3 с вульгарным ихтиозом, напоминающим фенотип ARCI [46]. На рис.…”