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Neonatal ichthyosis-sclerosing cholangitis syndrome (MONDO:0011874) is a rare autosomal recessive disorder characterized by congenital ichthyosis, sparse scalp hair, and variable hepatic involvement manifesting as sclerosing cholangitis or bile duct paucity. Pathogenic variants in CLDN1, encoding the tight junction component claudin-1, underlie this syndrome. Affected infants present with skin scaling, hypotrichosis or scarring alopecia, and cholestatic liver disease. Recognition of CLDN1 mutations has facilitated molecular diagnosis and expanded the phenotypic spectrum. Here we evaluate clinical validity, genetic evidence, and functional studies supporting CLDN1 as the causative gene for NISCh. This assessment guides diagnostic testing and informs future research. Key take-home: biallelic CLDN1 testing is essential in neonates with ichthyosis and cholestatic liver disease.
Homozygous dinucleotide deletions c.200_201del (p.Phe67_Val97del) in CLDN1 have been identified in four patients from two consanguineous Moroccan families and in three additional Moroccan brothers from a separate pedigree, all presenting with ichthyosis, hypotrichosis, and bile duct paucity (PMID:20645982). This recurrent variant suggests a founder effect in the Moroccan population. Clinical phenotypes included scarring alopecia in early infancy and cholestasis with duct paucity rather than overt sclerosing cholangitis.
A singleton Swiss patient harboring a homozygous 1-bp deletion c.358del (p.Val120fs) and a patient with a novel truncating variant c.53G>A (p.Trp18Ter) further delineate the spectrum of CLDN1 loss-of-function alleles in NISCh syndrome (PMID:20645982; PMID:16619213). To date, nine probands with biallelic truncating mutations have been reported.
More recently, a founder missense variant c.242G>A (p.Arg81His) has been identified in seven patients from four non-consanguineous North African Jewish families, broadening the genetic and phenotypic spectrum to include variable ectodermal and liver involvement (PMID:37814412). A carrier frequency of ~1:220 in this population supports a population-specific risk allele.
In total, 16 probands from at least nine families carry biallelic CLDN1 variants, including nine truncating alleles and seven missense changes. Major alleles include c.200_201del (p.Phe67_Val97del) and p.Arg81His, both with founder effects in North African ancestries. Variant classes encompass frameshift, nonsense, and missense consistent with loss-of-function mechanism.
Segregation analyses in consanguineous pedigrees demonstrated homozygosity of pathogenic CLDN1 alleles in seven additional affected relatives beyond index cases, confirming autosomal recessive inheritance (PMID:20645982; PMID:37814412). Haplotype studies of p.Arg81His underscore inheritance from a common ancestral allele.
Functional assays on p.Arg81His reveal decreased CLDN1 protein expression and mislocalization in HaCaT keratinocyte models via Western blotting and immunofluorescence, and deleterious conformational shifts predicted by 3D modelling (PMID:35920354). Transmission electron microscopy of patient skin demonstrates disrupted tight junction architecture, consistent with loss-of-function pathogenesis (PMID:37814412).
Collectively, strong clinical validity is established for CLDN1 in NISCh syndrome, supported by numerous unrelated probands, segregation data, and concordant functional studies. The inheritance is autosomal recessive, with variants resulting in haploinsufficiency of claudin-1. Molecular testing of CLDN1 facilitates early diagnosis and genetic counseling. These findings are of diagnostic and research utility and may guide therapeutic interventions targeting tight junction biology.
Gene–Disease AssociationStrong16 probands across multiple families, 7 additional affected relatives segregating, concordant functional data Genetic EvidenceStrong16 probands with biallelic CLDN1 variants (9 truncating, 7 missense) in distinct populations, segregation in 7 relatives Functional EvidenceModerateIn vitro studies (3D modelling, Western blot, immunofluorescence) and TEM demonstrate CLDN1 loss-of-function |