Multi-Gene Next-Generation Sequencing for Molecular Diagnosis of Autosomal Recessive Congenital Ichthyosis: A Genotype-Phenotype Study of Four Italian Patients.

Tiziana Fioretti,Adelaide Ambrosio,Gabriella Esposito,Luigi Auricchio,Giuseppina Vitiello,Rosario Ammendola,Fabio Cattaneo,Angelo Piccirillo

doi:10.3390/diagnostics10120995

Abstract

Autosomal recessive congenital ichthyoses (ARCI) are rare genodermatosis disorders characterized by phenotypic and genetic heterogeneity. At least fourteen genes so far have been related to ARCI; however, despite genetic heterogeneity, phenotypes associated with mutation of different ARCI genes may overlap, thereby making difficult their clinical and molecular classification. In addition, molecular tests for diagnosis of such an extremely rare heterogeneous inherited disease are not easily available in clinical settings. In the attempt of identifying the genetic cause of the disease in four Italian patients with ARCI, we performed next-generation sequencing (NGS) analysis targeting 4811 genes that have been previously linked to human genetic diseases; we focused our analysis on the 13 known ARCI genes comprised in the panel. Nine different variants including three novel small nucleotide changes and two novel large deletions have been identified and validated in the ABCA12, ALOX12B, CYP4F22, and SULT2B1 genes. Notably, two patients had variants in more than one gene. The identification and validation of new pathogenic ABCA12, ALOX12B, CYP4F22, and SULT2B1 variants through multi-gene NGS in four cases of ARCI further highlight the importance of these genes in proper skin function and development.

Highlights

Autosomal recessive congenital ichthyoses (ARCI) are clinically and genetically heterogeneous nonsyndromic inherited disorders of keratinization with variable severity, characterized by skin scaling and hyperkeratosis of varying degree [1,2]
Diagnostics 2020, 10, 995 membrane sheds, the underlying skin phenotype can range from harlequin ichthyosis (HI) to lamellar ichthyosis (LI), characterized by dark plate-like scales, and congenital ichthyosiform erythroderma (CIE), with fine whitish scaling and variable erythroderma [5]
To identify the genetic cause of ARCI in four Italian patients, we used a multi-gene next-generation sequencing (NGS) assay targeting most genes related to Mendelian disorders, including 13 of the 14 genes hitherto associated with ARCI

Summary

Introduction

Autosomal recessive congenital ichthyoses (ARCI) are clinically and genetically heterogeneous nonsyndromic inherited disorders of keratinization with variable severity, characterized by skin scaling and hyperkeratosis of varying degree [1,2]. ARCI newborns often present the collodion membrane, which may cause serious perinatal complications, leading in some cases to infant mortality [3,4]. Diagnostics 2020, 10, 995 membrane sheds, the underlying skin phenotype can range from harlequin ichthyosis (HI) to lamellar ichthyosis (LI), characterized by dark plate-like scales, and congenital ichthyosiform erythroderma (CIE), with fine whitish scaling and variable erythroderma [5]. Collodion shedding leaves minor or no skin impairment, as in the self-improving collodion ichthyosis (SICI) [2,6]. Among ARCI, HI represents the most severe phenotype and is often lethal; even less severe types of ARCI may negatively influence patients’ quality of life [7,8]

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Results

Conclusion