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

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.

Copy number variation characterization and possible candidate genes in miscarriage and stillbirth by next‐generation sequencing analysis

“… 58 Variants in the serine peptidase inhibitor Kazal type 5 ( SPINK5 ) gene are involved in the molecular etiology of congenital ichthyosis. 59 Microdeletions in neuroligin 4 X‐linked ( NLGN4X ) gene can affect neurodevelopment. 60 Microduplications and microdeletions in the par‐3 family cell polarity regulator ( PARD3 ) gene are known to be related to neural tube defects.…”

Ichthyosis vulgaris: An updated review

“…There is also no hair loss, changes in the nails, or onychauxis. White seborrhoeic plagues are other common sights on the extremities 43 …”

“…Atopic disease is reported in 35%–70% of patients with ichthyosis vulgaris, 49 with more than 50% of them having atopic dermatitis 1 . Pruritus, allergic rhinoconjunctivitis, hypohidrosis, heat intolerance, and recurrent infections due to a disturbed skin barrier are other common occurrences 43 …”

“…White seborrhoeic plagues are other common sights on the extremities. 43 Süßmuth et al stated that since ichthyosis vulgaris is a non-syndromic form of ichthyosis, there is no extracutaneous involvement of the eyes, ears, olfactory, skeletal, and the nervous systems. 1,43 However, another study mentioned keratoconus and ectropion as ocular manifestations in a male patient.…”

“…Dry skin, whitish to light brown skin flakes due to peeling 43 and fine grey or whitish scales 1 have a primarily extensor distribution. 4 The extensor surfaces of the upper and lower extremities are the initial target 43 but the lower abdomen, feet, and soles may also be affected. 9 , 17 , 46 The flexural creases, however, are spared.…”