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.