CEP57 – Mosaic Variegated Aneuploidy Syndrome

Mosaic variegated aneuploidy (MVA) syndrome is a rare autosomal recessive disorder characterized by constitutional chromosome gains and losses, pre‐ and postnatal growth retardation, microcephaly, facial dysmorphism, and developmental delay. Biallelic loss‐of‐function variants in CEP57 have been identified as a causative mechanism, with multiple unrelated families demonstrating truncating or splice site mutations leading to centrosome dysfunction (PMID:21552266).

Autosomal recessive inheritance is confirmed by homozygosity or compound heterozygosity in six probands across four unrelated families, with segregation of pathogenic variants in four additional affected relatives (PMID:30010053; PMID:32861809; PMID:35434947; PMID:36635612).

The variant spectrum in CEP57 is exclusively protein‐truncating or splice disrupting: 11 unique loss‐of‐function alleles have been reported, including recurrent c.915_925dup (p.Leu309ProfsTer9) observed in Mexican and Moroccan pedigrees suggesting a local founder effect (PMID:30010053; PMID:32861809). Additional alleles include c.312T>G (p.Arg81Ter), c.382+2T>C, c.20_21del (p.Ser7fs), c.46-2A>T, and multiple nonsense and frameshift changes cataloged in initial discovery cohorts (PMID:21552266).

Clinical features across CEP57‐related MVA include severe intrauterine growth restriction (HP:0001511), postnatal short stature (HP:0004322), microcephaly (HP:0000252), brachydactyly (HP:0001156), dental anomalies (HP:0000164), facial dysmorphism (HP:0000271), rhizomelic limb shortening, narrow thorax, and variable respiratory insufficiency (PMID:30010053; PMID:35434947).

Functional studies demonstrate that CEP57 encodes a centrosomal scaffold essential for microtubule nucleation and mitotic chromosome stability. Loss‐of‐function alleles abrogate liquid–liquid phase separation and centrosome maturation in human cells, recapitulating aneuploidy phenotypes and rescuable by wild‐type CEP57 expression (PMID:21552266; PMID:38857398).

Together, genetic and experimental data yield a Strong level of clinical validity: six probands, segregation in four relatives, and concordant mechanistic evidence. CEP57 testing informs molecular diagnosis of MVA and guides genetic counseling in autosomal recessive pedigrees.

Key Take-home: Biallelic truncating or splice variants in CEP57 cause MVA syndrome via loss of centrosomal function, supporting targeted genetic testing in growth‐retarded, microcephalic patients.

References

• Nature genetics • 2011 • Mutations in CEP57 cause mosaic variegated aneuploidy syndrome. PMID:21552266
• European journal of medical genetics • 2019 • A homozygous CEP57 c.915_925dupCAATGTTCAGC mutation in a patient with mosaic variegated aneuploidy syndrome with rhizomelic shortening in the upper and lower limbs and a narrow thorax. PMID:30010053
• European journal of medical genetics • 2020 • Follow-up of two adult brothers with homozygous CEP57 pathogenic variants expands the phenotype of Mosaic Variegated Aneuploidy Syndrome. PMID:32861809
• Molecular genetics & genomic medicine • 2022 • A novel CEP57 variant associated with mosaic variegated aneuploidy syndrome in a Chinese female presenting with short stature, microcephaly, brachydactyly, and small teeth. PMID:35434947
• 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
• Proceedings of the National Academy of Sciences • 2024 • Cep57 regulates human centrosomes through multivalent interactions. PMID:38857398

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