ESCO2 – Roberts-SC phocomelia syndrome

Roberts-SC phocomelia syndrome is a rare autosomal recessive cohesinopathy characterized by pre- and postnatal growth retardation, tetraphocomelia, craniofacial dysmorphism including microcephaly, and characteristic cytogenetic findings of premature centromere separation. The disorder is allelic with SC phocomelia and results from biallelic loss-of-function variants in ESCO2, which encodes an acetyltransferase essential for establishment of sister chromatid cohesion during S phase. Clinical presentation ranges from lethal neonatal forms to milder adult survivors with variable limb and facial anomalies.

Genetic analyses across multiple cohorts have identified truncating and splice-site variants in ESCO2 in over 49 affected individuals from more than 20 unrelated families (autosomal recessive inheritance). A recurrent homozygous splice donor mutation c.1131+1G>A (p.?) has been observed in diverse populations [PMID:24864645]. Additional variant classes include frameshifts (e.g., c.760dup (p.Thr254fs)), nonsense changes (e.g., c.1075C>T (p.Gln359Ter)), and canonical splice mutations (e.g., c.1673+1G>A). These biallelic pathogenic alleles consistently segregate with disease, confirming loss of ESCO2 function as the underlying mechanism [PMID:16380922].

Segregation analyses demonstrate that affected individuals are either homozygous or compound heterozygous for ESCO2 variants, with parents uniformly heterozygous carriers and unaffected. No reports of dominant transmission or de novo variants have been described, and no additional affected relatives beyond index cases have been documented.

Functional studies reveal that ESCO2 loss leads to defective sister chromatid cohesion at heterochromatic regions, reduced auto-acetyltransferase activity, impaired proliferation, and hypersensitivity to DNA damaging agents. Cell lines from Roberts syndrome patients show increased aneuploidy, mitotic delays, and DNA damage response defects. Animal models in medaka and zebrafish recapitulate core phenotypes including limb reduction and craniofacial anomalies, and uncover tissue-specific variability in cohesion establishment [PMID:18411254, PMID:26044958].

Genotype–phenotype correlation studies indicate no strict relationship between mutation type and clinical severity; truncating alleles underlie both severe Roberts syndrome and milder SC phocomelia, defining a continuous spectrum. Variable expressivity is likely influenced by residual cohesion activity and modifiers of nonsense-mediated decay efficiency [PMID:16380922].

Integration of genetic and experimental evidence supports a Definitive gene–disease association. ESCO2 testing enables molecular diagnosis, carrier screening, and prenatal risk assessment for families at risk of Roberts-SC phocomelia syndrome. Key take-home: Biallelic ESCO2 loss-of-function is definitively causal for Roberts-SC phocomelia syndrome, justifying inclusion of ESCO2 in diagnostic and carrier panels.

References

• American Journal of Human Genetics • 2005 • Inactivating mutations in ESCO2 cause SC phocomelia and Roberts syndrome: no phenotype-genotype correlation. PMID:16380922
• Nature Genetics • 2005 • Roberts syndrome is caused by mutations in ESCO2, a human homolog of yeast ECO1 that is essential for the establishment of sister chromatid cohesion. PMID:15821733
• Human Molecular Genetics • 2008 • The molecular mechanism underlying Roberts syndrome involves loss of ESCO2 acetyltransferase activity. PMID:18411254
• Disease Models & Mechanisms • 2015 • Variations in dysfunction of sister chromatid cohesion in esco2 mutant zebrafish reflect the phenotypic diversity of Roberts syndrome. PMID:26044958
• JPMA • 2014 • The Roberts syndrome: a case report of an infant with valvular aortic stenosis and mutation in ESCO2. PMID:24864645

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