The EVC2 gene is one of two genes, defects in which lead to the development of Ellis-van Creveld syndrome. This autosomal recessive disease is characterized by the clinical tetrad of chondrodystrophy, polydactyly, ectodermal dysplasia, and cardiac anomalies. It is not clear how EVC and EVC2 genes contribute to the development of this condition. However, recent research has shown that the gene is active in the embryonic and fetal stages, and plays an important role in the development of organs, such as the heart, kidneys, and lungs, apart from bones. A mutation in the EVC gene is also responsible for a milder condition called Weyers acrodental dysostosis. This is an autosomal dominant disease that combines facial abnormalities with limb defects.
The EVC2 gene is located on chromosome 4p16. It spans a length of 217 kb. The EVC2 protein is predicted to be a multi pass membrane protein, consisting of 1308 amino acids, and weighing 147 kDa. At least three different isoforms of the protein are known to exist. More than 20 mutations in the EVC2 gene have been associated with the development of Ellis-van Creveld syndrome. However, only one mutation, 3793delC, is associated with Weyers acrodental dysostosis.
Temtamy et al. (2008) reported affected individuals with both the EVC and EVC2 genes inactivated on each allele. Affected subjects were born to a consanguineous family diagnosed with EvC and borderline intelligence. Temtamy et al. (2008) detected a 520-kb homozygous deletion comprising EVC, EVC2, C4orf6, and STK32B, caused by recombination between long interspersed nuclear element-1 (LINE-1 or L1) elements. Patients homozygous for the deletion are deficient in EVC and EVC2 and have no increase in the severity of the EvC typical features. Similarly deletion carriers demonstrate absence of digenic inheritance in EvC. Temtamy et al. (2008) suggested that the EVC-STK32B deletion also leads to mild mental retardation and reveals that loss of the novel genes C4orf6 and STK32B causes at most mild mental deficit. In an EvC compound heterozygote of different ethnic origin, Temtamy et al. (2008) identified the same LINE-to-LINE rearrangement due to a different recombination event.
[See also: United Arab Emirates > Ali et al., 2010].
Shaheen et al. (2013) determined the underlying gene defect in 18 Saudi families affected by Meckel-Gruber syndrome (MKS). All 18 families recruited to the study were consanguineous. DNA was obtained from both affected and unaffected members. When an autozygome guided mutation analysis of known MKS genes failed to uncover any mutations in some of the families, an exome sequencing was carried out. Exomes were then searched for compound heterozygous mutations in known MKS genes. Failing that, all detected variants were filtered for homozygous novel changes within the autozygome. By this approach, a novel mutation was identified in EVC2, c.3870_3893dup (p.Lys1293_Lys1300dup). This mutation was not found in dbSNP, 1000 genomes or 200 Saudi controls. EVC2 had not previously been associated with MKS, and hence, this investigation helped expand the genetic heterogeneity of the disorder.
Ali et al. (2010) studied patients presenting with features typical of Ellis-van Creveld syndrome. Mutation analysis in a patient born to consanguineous Emirati parents of Yemeni origin identified a novel splice site mutation (c.2047-1G>T) in intron 13 of the EVC2 gene in the affected patient. Hundred ethically matched control subjects were found not to have this mutation. The parents were found to be heterozygous for the mutation. In addition, another patient, born to Egyptian parents was detected to have a separate mutation (c.981delG; p.K327fs) in exon 8 of the EVC2 gene. This mutation has previously been reported. In this case too, the parents were heterozygous for the mutation, although they were unrelated.
[See: United Arab Emirates > Ali et al., 2010].