NECTIN4 – Ectodermal Dysplasia-Syndactyly Syndrome

Ectodermal dysplasia-syndactyly syndrome (EDSS1) is a rare autosomal recessive disorder characterized by hair and nail dysplasia, enamel hypoplasia, and cutaneous syndactyly due to biallelic variants in NECTIN4 (PVRL4) (HGNC:19688; MONDO:0013311).

Genetic analyses in multiple consanguineous and outbred families have identified homozygous and compound heterozygous missense, nonsense, splice-site, and frameshift NECTIN4 variants in >30 affected individuals from >10 unrelated families. Initial homozygosity mapping in an Algerian kindred and an Italian sibling pair revealed a splice donor mutation (c.1233+1G>A) and missense (c.554C>T (p.Thr185Met)) alongside a frameshift (c.906del (p.Pro304fs)) ([PMID:20691405]). Subsequent reports include a novel c.247C>T (p.His83Tyr) variant in a Turkish child ([PMID:29456479]), a recurrent nonsense c.181C>T (p.Gln61Ter) allele in a Kashmiri family ([PMID:37829154]), and two novel extracellular-domain mutations (c.79+1G>A; c.680A>G (p.His227Arg)) segregating in six patients from two families ([PMID:40586252]). Additional truncating and missense variants (e.g., c.163C>T (p.Arg55Ter); c.242T>C (p.Leu81Pro)) have been described in Pakistani kindreds (PMIDs:37183149; 29430627) and expanded the mutational spectrum.

Segregation analysis demonstrates perfect cosegregation of biallelic NECTIN4 variants with EDSS1 in at least 12 affected relatives across multiple families, supporting autosomal recessive inheritance. Carrier frequencies remain unreported but variants are absent from population databases and in-house exomes from the same ethnicities.

Functional studies in patient keratinocytes and epithelial cell models confirm that pathogenic NECTIN4 variants impair nectin-4 binding to nectin-1, disrupt cadherin-based adherens junction formation, and delay Rac1 activation, recapitulating cutaneous and hair follicle defects (c.554C>T (p.Thr185Met)) ([PMID:24577405]). High nectin-4 expression in murine digit and hair follicle epithelia and rescue experiments further validate haploinsufficiency of cell-cell adhesion as the disease mechanism.

No conflicting evidence has been reported to date, and phenotypic variability (e.g., upper lip cleft) likely reflects allelic heterogeneity rather than distinct etiologies. The strong concordance of clinical, genetic, and functional data across diverse populations establishes a definitive gene-disease relationship.

Key Take-home: Biallelic NECTIN4 variants reliably diagnose EDSS1, enabling carrier testing, prenatal diagnosis, and targeted functional assays for clinical management.

References

• American journal of human genetics • 2010 • Mutations in PVRL4, encoding cell adhesion molecule nectin-4, cause ectodermal dysplasia-syndactyly syndrome. PMID:20691405
• Molecular syndromology • 2017 • A Novel Missense Variant in the PVRL4 Gene Underlying Ectodermal Dysplasia-Syndactyly Syndrome in a Turkish Child. PMID:29456479
• Genetics research • 2023 • A Recurrent Nonsense Mutation in NECTIN4 Underlying Ectodermal Dysplasia-Syndactyly Syndrome with a Novel Phenotype in a Consanguineous Kashmiri Family. PMID:37829154
• The Israel Medical Association journal : IMAJ • 2025 • Novel NECTIN4 Mutations in Ectodermal Dysplasia Syndactyly Syndrome in Two Families. PMID:40586252
• The Journal of investigative dermatology • 2014 • Nectin-4 mutations causing ectodermal dysplasia with syndactyly perturb the rac1 pathway and the kinetics of adherens junction formation. PMID:24577405

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