CEP57 – Mosaic Variegated Aneuploidy Syndrome 2

Mosaic Variegated Aneuploidy Syndrome 2 (MVA2) is a rare autosomal recessive disorder caused by biallelic loss-of-function variants in CEP57. Affected individuals present with prenatal‐onset growth delay, facial dysmorphism, short stature, congenital heart defects, and skeletal anomalies. The CEP57–mosaic variegated aneuploidy syndrome 2 association is supported by multiple unrelated probands and concordant functional studies.

Initial descriptions included 10 patients with homozygous intragenic duplication c.915_925dup11 (10/13 alleles) demonstrating recurrent LOF (PMID:34500087). Two Moroccan cases carrying c.915_925dup11 and two Indian siblings with a novel homozygous splice‐site variant c.382+2T>C (p.Ser?; donor loss) expand the variant spectrum to five distinct alleles in 14 probands across 11 families (PMID:34500087; PMID:36635612). Additional frameshift and nonsense variants (e.g., c.973C>T (p.Arg81Ter)) have been reported in consanguineous pedigrees.

Segregation analyses in consanguineous families demonstrate cosegregation of homozygous LOF alleles with disease in siblings, confirming autosomal recessive inheritance (PMID:36635612). No unaffected homozygotes have been reported, and carrier parents remain asymptomatic.

Functional studies establish CEP57 as a centrosomal scaffold essential for microtubule nucleation and chromosomal stability. Exome sequencing with cellular assays showed patient‐derived LOF variants lead to mosaic aneuploidy and mitotic errors (PMID:21552266). Recent work reveals CEP57 undergoes LLPS and mediates centrosome maturation via multivalent interactions; truncating variants disrupt condensate formation and microtubule aster assembly (PMID:38857398).

No studies dispute the CEP57–MVA2 link, although phenotypic overlap with Noonan syndrome mandates comprehensive molecular testing to avoid misdiagnosis (PMID:36588761).

Integrating genetic and functional data, biallelic LOF variants in CEP57 are robustly associated with MVA2 (Strong). Clinical utility is high: molecular diagnosis informs prognosis and management, and growth‐hormone therapy is ineffective in MVA2 due to fundamental centrosomal defects.

References

• Clinical genetics • 2023 • Mosaic variegated aneuploidy syndrome 2 with biallelic novel CEP57 splice site variation in Indian siblings: Expanding the clinical and molecular spectrum. PMID:36635612
• European journal of medical genetics • 2021 • Mosaic Variegated Aneuploidy syndrome 2 caused by biallelic variants in CEP57, two new cases and review of the phenotype. PMID:34500087
• Nature Genetics • 2011 • Mutations in CEP57 cause mosaic variegated aneuploidy syndrome. PMID:21552266
• Proceedings of the National Academy of Sciences of the United States of America • 2024 • Cep57 regulates human centrosomes through multivalent interactions. PMID:38857398
• The Journal of clinical investigation • 2020 • BubR1 allelic effects drive phenotypic heterogeneity in mosaic-variegated aneuploidy progeria syndrome. PMID:36588761

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