Novel Homozygous Mutations in the Genes TGM1, SULT2B1, SPINK5 and FLG in Four Families Underlying Congenital Ichthyosis.

Fozia Fozia,Muhammad Sohaib,Siddique A Ansari,Sher Alam Khan,Abdul Nasir,Abdulrahman Alobaid,Sulman Basit,Ahmed Bari,Saadullah Khan,Hafiz Majid Mahmood,Riaz Ullah,Rubina Nazli

doi:10.3390/genes12030373

Abstract

Background: Ichthyoses are a large group of hereditary cornification disorders, which are both clinically and etiologically heterogeneous and affect mostly all the skin surface of the patients. Ichthyosis has its origin in an ancient Greek word “ichthys” meaning fish, this is because the ichthyosis patients have dry, thickened, and scaly skin. There is an excess accumulation of epidermal cells resulting in the appearance of continuous and widespread scales on the body. There are many varieties of ichthyosis with a broad spectrum of intensity, severity, and associated symptoms, most of them are extremely rare. Ichthyosis vulgaris is the most frequently occurring type of ichthyoses. Method: The present study consists of four Pakistani ichthyosis families (A, B, C, and D). Whole exome sequencing (WES) approach was used to identify the pathogenic sequence variants in probands. The segregation of these variants in other participants was confirmed by Sanger sequencing. Results: Total four variants including, two splice site (TGM1: c.2088 + 1G > A) and (SPINK5: c.882 + 1G > T), a missense (SULT2B1: c.419C > T; p. Ala140Val), and a nonsense (FLG: c.6109C > T; p. Arg2037Ter) variant were identified in families A, C, B, and D, respectively, as causative mutations responsible for ichthyosis in these families. Conclusion: Our study unravels the molecular etiology of the four Pakistani ichthyosis families and validates the involvement of TGM1, SULT2B1, SPINK5, and FLG, in the etiology of different forms of ichthyosis. In addition, this study also aims to give a detailed clinical report of the studied ichthyosis families.

Highlights

Congenital ichthyoses are a large group of genetic abnormalities having defective cornification of the skin as a hallmark
Following the recommendations of Helsinki declarations this research study was approved by the Ethical Review Committee (ERC) of Institute of Basic Medical Sciences (IBMS), Khyber Medical University (KMU), Peshawar, Ethical code no Dir/KMUEB/HM/000741/Dated 8/10/2020 and Ethical and Research Committee of Kohat University of Science and Technology (KUST), Kohat, Khyber Pakhtunkhwa Pakistan, Ref.No.VCKUST/ethicalcommittee/16-25/26.04.2016
They were suffering from pruritus, anhidrosis, heat intolerance, lack of skin elasticity, and recurrent skin infections

Summary

Introduction

Congenital ichthyoses are a large group of genetic abnormalities having defective cornification of the skin as a hallmark. Ichthyoses are categorized into nonsyndromic/isolated and syndromic forms, based on their pathophysiology, clinical manifestations, and mode of inheritance. They are inherited in autosomal recessive, autosomal dominant, and X-linked forms [1,2]. The stratum granulosum and stratum corneum are malformed and do not exhibit their normal characteristics, that can be distinguished based on their clinical manifestations, histological findings, structural and biochemical abnormalities of the epidermis as well as genetic etiology [3,4]. Whole exome sequencing (WES) approach was used to identify the pathogenic sequence variants in probands. Conclusion: Our study unravels the molecular etiology of the four Pakistani ichthyosis families and validates the involvement of TGM1, SULT2B1, SPINK5, and FLG, in the etiology of different forms of ichthyosis. This study aims to give a detailed clinical report of the studied ichthyosis families

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