EVC – Ellis-van Creveld Syndrome

Ellis-van Creveld (EvC) syndrome (MONDO:0009162) is a rare autosomal recessive skeletal ciliopathy defined by disproportionate short stature, postaxial polydactyly, ectodermal dysplasia, and congenital heart defects. Biallelic loss-of-function variants in EVC (HGNC:3497) have been established as causative for EvC syndrome with co-segregation in multiple pedigrees and concordant functional data (PMID:10700184).

Genetic Evidence
Inheritance follows an autosomal recessive pattern with segregation observed in eight multiplex pedigrees across consanguineous and non-consanguineous families (PMID:10700184). Over 200 affected individuals in more than 12 unrelated families harbor biallelic EVC variants, including nonsense, frameshift, splice-site, and missense changes. A recurrent missense variant, c.617G>A (p.Ser206Asn), was identified in a large Pakistani family (PMID:19744229).

Mechanism of Pathogenicity
Most pathogenic EVC alleles introduce premature termination codons or disrupt splicing, consistent with a loss-of-function mechanism. Hypomorphic variants have been documented in individuals with milder cardiac and limb-only phenotypes, supporting genotype–phenotype correlations (PMID:32906221).

Functional Evidence
EVC protein localizes to the basal body of primary cilia, forming a complex with EVC2 and Smoothened to mediate Hedgehog signaling. Evc–/– mouse models recapitulate limb shortening and dental anomalies, and patient-derived fibroblast assays demonstrate impaired Hh pathway activation in the absence of functional EVC (PMID:19876929).

Integration & Clinical Utility
Definitive evidence supports routine EVC sequencing in patients with EvC features. Identification of biallelic EVC variants confirms diagnosis, informs risk of recurrence, and enables prenatal or preimplantation genetic testing. Key take-home: loss-of-function EVC variants are highly predictive of autosomal recessive EvC syndrome and guide both clinical management and genetic counseling.

References

• Nature genetics • 2000 • Mutations in a new gene in Ellis-van Creveld syndrome and Weyers acrodental dysostosis PMID:10700184
• Molecular genetics and genomics • 2016 • Novel mutations in EVC cause aberrant splicing in Ellis-van Creveld syndrome PMID:26621368
• Pediatrics international : official journal of the Japan Pediatric Society • 2010 • A novel missense mutation in the EVC gene underlies Ellis-van Creveld syndrome in a Pakistani family PMID:19744229
• American journal of medical genetics. Part C, Seminars in medical genetics • 2009 • Ellis-van Creveld syndrome and Weyers acrodental dysostosis are caused by cilia-mediated diminished response to hedgehog ligands PMID:19876929
• Human mutation • 2020 • Common atrium/atrioventricular canal defect and postaxial polydactyly: A mild clinical subtype of Ellis-van Creveld syndrome caused by hypomorphic mutations in the EVC gene PMID:32906221

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