NECTIN4 – Ectodermal dysplasia-syndactyly syndrome 1

Ectodermal dysplasia-syndactyly syndrome 1 (EDSS1) is a rare autosomal recessive disorder marked by hair anomalies, peg-shaped and conical teeth, and cutaneous fusion of fingers and toes. Biallelic variants in NECTIN4 (PVRL4), encoding the cell-cell adhesion molecule nectin-4, underlie EDSS1 through loss of adherens junction integrity and impaired ectodermal development ([PMID:20691405]).

To date, ≥10 probands from ≥4 unrelated consanguineous families have been reported with homozygous or compound heterozygous NECTIN4 variants. A novel nonsense mutation c.229C>T (p.Gln77Ter) was identified in a consanguineous kindred with typical EDSS1 features ([PMID:29265343]). A subsequent case described the frameshift variant c.1150delC (p.Gln384ArgfsTer7) in a 5.5-year-old female presenting brittle scalp hair, dental agenesis (HP:0009804), and minimal toe syndactyly (HP:0004779) ([PMID:34067522]). Segregation of pathogenic alleles in multiple pedigrees confirms autosomal recessive inheritance.

The NECTIN4 variant spectrum includes ≥5 nonsense changes (e.g., c.1117C>T (p.Arg373Ter)), ≥3 frameshift indels (e.g., c.906del (p.Pro304fs)), and ≥4 missense substitutions (p.Val242Met, p.Thr185Met, p.His83Tyr, p.Leu81Pro), affecting both extracellular Ig-like domains and the cytoplasmic tail.

Functional assays in primary keratinocytes and epithelial cell models demonstrate that missense alleles p.Val242Met and p.Thr185Met perturb nectin-1 clustering, delay adherens junction assembly, and impair Rac1 activation, consistent with deficient cell-cell adhesion ([PMID:24577405]).

No studies disputing the NECTIN4–EDSS1 link have been reported. The concordance of segregation, variant types, and mechanistic data support a loss-of-function disease mechanism.

Clinically, targeted NECTIN4 sequencing enables definitive diagnosis, carrier detection, and informed genetic counseling in families with EDSS1.

References

• American journal of human genetics • 2010 • Mutations in PVRL4, encoding cell adhesion molecule nectin-4, cause ectodermal dysplasia-syndactyly syndrome. PMID:20691405
• International journal of dermatology • 2018 • A novel homozygous mutation in PVRL4 causes ectodermal dysplasia-syndactyly syndrome 1. PMID:29265343
• Genes • 2021 • Ectodermal Dysplasia-Syndactyly Syndrome with Toe-Only Minimal Syndactyly Due to a Novel Mutation in NECTIN4: A Case Report and Literature Review. PMID:34067522
• 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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