MVA2 is caused by both copies of the CEP57 gene not functioning properly. This is due to biallelic changes (pathogenic variants in both paternal and maternal alleles of the gene) within CEP57 which disrupt its function. This condition affects boys and girls, and there are both mildly and more significantly affected individuals of both sexes.
CEP57, located on chromosome 11, encodes a protein called Translokin. This protein has a function in microtubule stabilization, being crucial for maintaining correct chromosomal number during cell division. The absence of functional CEP57 protein results in problems with the separation of chromosomes during cell division, leading to aneuploidy (abnormal number of chromosomes in a cell). It is interesting to point out that it has been also demonstrated a critical biological role for Cep57 in bone development and new blood vessel formation.
MVA2 syndrome is caused by germline homozygous (identical changes in both copies) or compound heterozygous (different changes in both copies) loss of function variants in CEP57 (NM_014679.4). All pathogenic variants reported to date in the CEP57 gene are predicted to cause protein truncation, with a recurrent mutation: c.915_925dup11. To date, no copy number variants (CNVs) in CEP57 have been reported in any MVA2 patient. Most pathogenic variants identified to date in CEP57 have been identified by whole exome sequencing, but direct Sanger sequencing of all exons of this gene has been also applied.
Mosaic aneuploidies on chromosome metaphases is a universal hallmark of MVA2 syndrome. Thus, the possibility of MVA2 should be considered if multiple mosaic aneuploidies are observed in the cytogenetic study of children with pre- and postnatal growth retardation associated with dysmorphic facial features and congenital malformations.
CEP57