CEP57, located on chromosome 11q21, encodes a cytoplasmic protein called Translokin. This protein localizes to the centrosome and has a function in microtubule stabilization. The N-terminal half of this protein is required for its centrosome localization and for its multimerization, and the C-terminal half is required for nucleating, bundling and anchoring microtubules to the centrosomes. This protein is crucial for maintaining correct chromosomal number during cell division, therefore the absence of functional CEP57 protein results in problems with spindle microtubule organization that may prevent the normal separation of chromosomes during cell division, leading to aneuploidy. 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 through its ability to interact with and regulate the abundance of basic fibroblast growth factor 2 (Fgf2), a key modulator of ossification and angiogenesis.
MVA2 syndrome is caused by germline homozygous or compound heterozygous 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, including nonsense and frameshift variants, with a recurrent mutation: c.915_925dup11 identified in 10 of the cases. 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. In several cases, the karyotype was reported as normal, despite the presence of variable mosaic aneuploidies that were interpreted as artefacts. 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. Lack of premature chromatid separation (PCS) might be a distinguishing feature between MVA2 and MVA1.