Variants in KLF4 affecting residue Asp441 cause a novel autosomal dominant syndromic ichthyosis

Summary: Abstract Body: Congenital ichthyoses comprise a group of skin scaling diseases with clinical and genetic heterogeneity. Among them, syndromic ichthyoses affect organs beyond the skin. In this study, we enrolled four unrelated patients with a novel form of syndromic ichthyosis to identify the causative gene and its underlying pathogenesis. The patients primarily presented with ichthyosis, palmoplantar keratoderma, hypotrichosis, periorificial keratosis, nail dystrophy, and various extracutaneous features, including sensorineural deafness, lower extremity lymphedema, and developmental defects of internal organs. Whole-exome sequencing identified two de novo heterozygous KLF4 variants, c.1322A>G (p.Asp441Gly) and c.1323T>A (p.Asp441Glu), in these patients, both affecting the Asp441 residue in the second zinc finger (ZF2) motif of KLF4. Structural modeling suggested that these variants destabilize the α-helix of ZF2. KLF4 is a transcription factor widely expressed in various tissues, including the skin. A reduced KLF4 expression in the patients’ skin was detected, and dual-luciferase reporter assays revealed impaired transcriptional activity of both variants. Skin organoids harboring the heterozygous c.1323T>A variant displayed defects in epithelial morphogenesis. RNA sequencing of these organoids revealed abnormal expression of keratinocyte differentiation-related genes, including reduced KLK7, a kallikrein-related peptidase crucial for skin desquamation. Consistently, KLK7 expression was downregulated in the patients’ skin. In conclusion, loss-of-function variants affecting residue Asp441 of KLF4 are associated with an autosomal dominant syndromic ichthyosis with multi-organ involvement. Our study highlights the essential role of KLF4 in regulating skin keratinization and its broader systemic impact. Zijuan Wang¹, Jun Liu², Oded Wechsberg³, Lina Liang², Catherine E. Keegan⁴, Christina Sloan-Heggen⁴, Huijun Wang², Zhimiao Lin² 1. Chinese Academy of Medical Sciences & Peking Union Medical College Plastic Surgery Hospital and Institute, Beijing, China. 2. Guangdong Provincial Dermatology Hospital, Guangzhou, China. 3. Schneider Children's Medical Center of Israel, Petah Tikva, Israel. 4. University of Michigan Medical School, Ann Arbor, MI, United States. Genetic Disease, Gene Regulation, Gene Therapy & Epigenetics