Next‐generation sequencing through multi‐gene panel testing for diagnosis of hereditary ichthyosis in Chinese

Abstract

Inherited ichthyoses are a heterogeneous group of rare disorders related to over 40 genes. To identify underlying molecular causes in inherited ichthyosis among Chinese and to correlate genotype and phenotype, 35 probands clinically diagnosed inherited ichthyosis, except ichthyosis vulgaris and X-linked ichthyosis, were included in our study. Molecular analysis was performed using next-generation sequencing (NGS) through multi-gene panel testing targeting all ichthyosis-related genes. Genetic variants causative for the ichthyosis were identified in 32 of 35 investigated patients.In all, 43 causative mutations across 12 genes were disclosed, including 16 novel variants. Thirteen keratinopathic ichthyosis, fourteen autosomal recessive congenital ichthyosis (ARCI) including one caused by mutations in SDR9C7, and five syndromic ichthyoses were confirmed. Four probands, with presumptive ARCI, turned out to be keratinopathic ichthyosis (2), neutral lipid storage disease (1), and Sjogren-Larsson syndrome (1), respectively. Next-generation technology has been demonstrated to be an effective tool in diagnosing inherited ichthyosis constituting a diverse group of cornification disorders. Our study further expands mutation spectrum and clinical phenotype associated with inherited ichthyosis in Chinese. K E Y W O R D S Chinese, congenital ichthyosis, mutation, next-generation sequence 1 | INTRODUCTION Inherited ichthyoses are genetic disorders characterized by generalized dry skin, scaling and hyperkeratosis with a broad spectrum of skin manifestations. 1 Inherited ichthyoses have now been scientifically divided into two groups (nonsyndromic ichthyosis and syndromic forms) and multiple subgroups. 1 Identification of molecular cause is required and very important for clinical diagnosis and prognosis, genetic counseling, prenatal genetic diagnosis, optimized treatment and drug development. 2 However, over 40 genes have been related with ichthyoses.Conventional first-generation sequencing is obviously not suitable for efficient molecular analysis. Up to date, at least four studies have been succeeded in applying next-generation sequencing (NGS) technology in molecular analysis of inherited ichthyoses. 2,3 We aimed to identify the underlying mutations in inherited ichthyoses of Chinese descent using NGS methods.

Knockdown of SDR9C7 Impairs Epidermal Barrier Function

“…However, according to the literature, 15 -20 % of patients with the ARCI diagnosis do not have pathogenic variants in any of the known genes. In 2016, Shigehara et al found pathogenic homozygous missense variants in SDR9C7 with lamellar ichthyosis in three consanguineous Lebanese families (Shigehara et al, 2016), and more recent reports of pathogenic variants in SDR9C7 in ARCI patients from Japan, Austria, Pakistan, France and China provide additional evidence on the role of this gene in pathogenesis of non-syndromic ichthyosis (Takeichi et al, 2017;Seidl-Philipp et al, 2019;Karim et al, 2017;Hotz et al, 2018; J o u r n a l P r e -p r o o f Mazereeuw-Hautier et al, 2020;Cheng et al, 2020;Simpson et al, 2020). However, these studies failed to identify genotype-phenotype correlations.…”

Case Report: Chanarin-Dorfman Syndrome: A Novel Homozygous Mutation in ABHD5 Gene in a Chinese Case and Genotype-Phenotype Correlation Analysis

“…The mutation found in this patient enriched our understanding of pathogenic mutations for CDS. As it is not easy to obtain an accurate diagnosis only based on the dermal features, a blood smear and mutational analysis are required for patients suspected with congenital ichthyosis ( Cheng et al, 2020 ).…”

Molecular Diagnosis of Neurofibromatosis by Multigene Panel Testing

“…It has a higher gene mutation detection rate. By applying multigene panel testing methods, the molecular cause has been successfully elucidated in 91% of 35 inherited ichthyosis patients (Cheng et al, 2020) and 90% of 40 suspected epidermolysis bullosa patients (Has et al, 2018). Although it is not a 100% discovery rate, there is undoubtedly an economic and a time advantage to panel genetic testing versus a stepwise approach, which is one of the alternative effective methods to help clinical diagnosis.…”