CLDN1 Arg81His founder variant causes ichthyosis, leukocyte vacuoles, alopecia, and sclerosing cholangitis (ILVASC) syndrome in Moroccan Jews

Marina Eskin-Schwartz, Vadim Dolgin, Elena Didkovsky, Ilana Aminov, Anna Pikovsky, Noam Hadar, Eyal Kristal, Galina Ling, Idan Cohen, Uri Zilberman, Ohad S. Birk

Research output: Contribution to journalArticlepeer-review

Abstract

Neonatal ichthyosis and sclerosing cholangitis syndrome (NISCH), also known as ichthyosis, leukocyte vacuoles, alopecia, and sclerosing cholangitis (ILVASC), is an extremely rare disease of autosomal recessive inheritance, resulting from loss of function of the tight junction protein claudin-1. Its clinical presentation is highly variable, and is characterized by liver and ectodermal involvement. Although most ILVASC cases described to date were attributed to homozygous truncating variants in CLDN1, a single missense variant CLDN1 p.Arg81His, associated with isolated skin ichthyosis phenotype, has been recently reported in a family of Moroccan Jewish descent. We now describe seven patients with ILVASC, originating from four non consanguineous families of North African Jewish ancestry (including one previously reported family), harboring CLDN1 p.Arg81His variant, and broaden the phenotypic spectrum attributed to this variant to include teeth, hair, and liver/bile duct involvement, characteristic of ILVASC. Furthermore, we provide additional evidence for pathogenicity of the CLDN1 p.Arg81His variant by transmission electron microscopy of the affected skin, revealing distorted tight junction architecture, and show through haplotype analysis in the vicinity of the CLDN1 gene, that this variant represents a founder variant in Jews of Moroccan descent with an estimated carrier frequency of 1:220.

Original languageAmerican English
Pages (from-to)44-51
Number of pages8
JournalClinical Genetics
Volume105
Issue number1
DOIs
StatePublished - 1 Jan 2024

Keywords

  • Arg81His
  • CLDN1
  • ILVASC
  • Moroccan Jews
  • cholestasis
  • founder variant
  • ichthyosis
  • neonatal ichthyosis and sclerosing cholangitis syndrome

All Science Journal Classification (ASJC) codes

  • Genetics(clinical)
  • Genetics

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