Whole Exome Sequencing Identifies Novel Pathogenic Variants in TGM1 and ALOX12B in Patients with Hereditary Ichthyosis

Abstract

Abstract Background Hereditary ichthyosis is a clinically and genetically heterogeneous disorder of keratinization, characterized by cutaneous hyperkeratosis of the skin. Mutations in over 50 genes have been identified to be associated with hereditary ichthyosis. Establishing an accurate diagnosis is important for genetic counseling and patient management. Objective We aimed to assess the clinical applicability of whole-exome sequencing (WES) in the molecular diagnosis of hereditary ichthyosis. Methods During a 1-year period, index cases of 5 unrelated families clinically diagnosed with hereditary ichthyosis went through WES, followed by extensive segregation analysis to assess the pathogenicity of the detected variants, and prenatal diagnosis, where indicated. Results In this case series, we identified 2 homozygous variants (c.655A > G and c.797A > G) and one heterozygous (c.428G > A) variant in TGM1 and 2 homozygous variants (c.527 + 2T > G and c.1654G > T) in ALOX12B, 4 of which were novel. The variants were all pathogenic/likely pathogenic according to the ACMG classification and segregation analysis, except for c.797A > G in TGM1 which was a variant of unknown clinical significance. Prenatal diagnosis was performed in Family 1 with c.655A > G in TGM1 and Family 2 with c.527 + 2T > G in ALOX12B. Conclusion Our findings further support that WES is an effective diagnostic tool for the accurate and rapid identification of causative variants in hereditary ichthyosis.