CNTNAP1 – Lethal Congenital Contracture Syndrome Type 7

CNTNAP1 encodes contactin-associated protein 1, a key paranodal component essential for saltatory conduction and proper axo-glial junction formation. Bi-allelic loss-of-function variants in CNTNAP1 underlie lethal congenital contracture syndrome type 7 (LCCS7), an autosomal recessive condition marked by severe neonatal hypotonia, polyhydramnios, arthrogryposis multiplex congenita, facial diplegia, and early mortality (CNTNAP1; Lethal congenital contracture syndrome type 7).

Clinical Validity

The association meets a Moderate ClinGen rating. A single nonconsanguineous Lebanese proband with a homozygous premature stop variant was reported (1 proband) (PMID:32328110); an additional four unrelated families harbor homozygous frameshift variants presenting with congruent congenital contracture and neuropathy features (4 probands) (PMID:24319099). No conflicting reports have been described.

Genetic Evidence

Inheritance is autosomal recessive with no observed phenotypes in heterozygous carriers. Reported variants are predominantly early truncating alleles: c.3361C>T (p.Arg1121Ter) (case report) (PMID:32328110), and multiple homozygous frameshift/stop‐gain variants in NM_003632.3 (e.g., c.1852C>T (p.Arg618Ter), c.3767_3768del (p.Leu1256fs), c.2503C>T (p.Arg835Ter), c.3009dup (p.Glu1004Ter)) observed across four families (PMID:24319099). Total probands: 5, all with concordant clinical presentations.

Functional / Experimental Evidence

Loss of CNTNAP1 disrupts paranodal junctions, leading to everted myelin loops and failure of action potential propagation. Cntnap1C324R and Cntnap1R765C mouse models recapitulate hypomyelinating neuropathy, weight loss, reduced nerve conduction, and motor dysfunction; postnatal transgenic expression rescues axonal domain organization and motor deficits (PMID:37862170). A knock-in Cntnap1G350V/null model mimics human truncation co-allelic pathology and is fully rescued by wild type transgene expression (PMID:40265789).

Integration & Conclusion

Collectively, bi-allelic CNTNAP1 loss-of-function variants cause LCCS7 through paranodal disorganization and hypomyelination. The genetic and functional data are concordant, with animal rescue experiments providing strong mechanistic support. Additional genetic segregation data and natural history studies may further solidify the definitive classification.

Key Take-home: CNTNAP1 biallelic truncating variants reliably predict LCCS7 risk, informing early genetic diagnosis and potential future gene-based therapies.

References

• Case reports in medicine • 2020 • CNTNAP1 Mutations and Their Clinical Presentations: New Case Report and Systematic Review. PMID:32328110
• Human molecular genetics • 2014 • Mutations in CNTNAP1 and ADCY6 are responsible for severe arthrogryposis multiplex congenita with axoglial defects. PMID:24319099
• Cell Reports • 2023 • Mouse models of human CNTNAP1-associated congenital hypomyelinating neuropathy and genetic restoration of murine neurological deficits. PMID:37862170
• Journal of Neuroscience Research • 2025 • A Novel Mutation in CNTNAP1 Gene Causes Disorganization of Axonal Domains, Hypomyelination and Severe Neurological Deficits. PMID:40265789

Evidence Based Scoring (AI generated)