EVC2 – Ellis-van Creveld Syndrome

Ellis-van Creveld syndrome (EvC; MONDO:0009162) is a rare autosomal recessive chondrodysplastic dysplasia characterized by disproportionate short stature, postaxial polydactyly, nail dysplasia, dental anomalies, and congenital heart defects. Biallelic loss-of-function variants in EVC2 underlie a substantial proportion of EvC cases, complementing pathogenic EVC mutations. The inheritance is firmly autosomal recessive, with multiple consanguineous families demonstrating segregation of EVC2 null alleles with disease.

1 Clinical Validity

The gene–disease association between EVC2 and EvC is categorized as Strong. This is justified by identification of biallelic EVC2 variants in 25 unrelated probands, 22 of whom carry two truncating/splice variants ([PMID:17024374]). Segregation of EVC2 mutations across at least two consanguineous pedigrees further supports causality ([PMID:26580685]). Concordant functional data demonstrate loss of primary cilia localization and impaired Hedgehog signaling for EVC2 mutants.

2 Genetic Evidence

Over 25 probands with EvC harbor biallelic EVC2 variants, including nonsense, frameshift, and splice-site mutations in trans. The variant spectrum comprises 18 truncating alleles (e.g., c.3265C>T (p.Gln1089Ter)) and multiple splice-site changes. A recurrent founder variant p.Trp314Ter has been observed in unrelated Middle Eastern and South Asian families. Segregation analysis in sib pairs confirms autosomal recessive transmission with 2 additional affected relatives in two families ([PMID:26580685]).

3 Functional Evidence

EVC2 encodes a basal body component of the EvC complex that modulates Hedgehog pathway output. Loss-of-function EVC2 alleles abrogate EVC complex entry into primary cilia and impair downstream GLI activation in patient fibroblasts and mouse embryonic fibroblast models, consistent with EvC phenotypes ([PMID:19876929]). These assays provide Moderate functional support for haploinsufficiency as the mechanism.

4 Conflicting Evidence

No studies to date dispute the role of EVC2 in EvC syndrome. Genetic heterogeneity has been reported, but EVC2 variants consistently produce the classic EvC tetrad without alternative phenotypes.

5 Integration and Clinical Utility

Combined genetic and functional data establish EVC2 as a bona fide EvC gene. Molecular testing for EVC2 should be included in diagnostic panels for skeletal ciliopathies and congenital heart defects. Identification of truncating EVC2 alleles enables accurate recurrence risk counseling and prenatal diagnosis. Key Take-home: Biallelic EVC2 loss-of-function variants cause autosomal recessive Ellis-van Creveld syndrome, with strong genetic and experimental evidence supporting clinical testing and family planning.

References

• Molecular Genetics and Metabolism • 2002 • A new gene, EVC2, is mutated in Ellis-van Creveld syndrome. PMID:12468274
• Human Genetics • 2007 • Sequencing EVC and EVC2 identifies mutations in two-thirds of Ellis-van Creveld syndrome patients. PMID:17024374
• 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
• Clinical Dysmorphology • 2016 • Novel homozygous mutations in the EVC and EVC2 genes in two consanguineous families segregating autosomal recessive Ellis-van Creveld syndrome. PMID:26580685

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