Submission Details

ESCO2 encodes an N-acetyltransferase, which targets the SMC3 cohesin subunit, and is necessary for proper sister chromatid cohesion during DNA replication and double-strand breaks repair. ESCO2 was first reported in relation to autosomal recessive Roberts syndrome and SC phocomelia syndrome in 2005 (Vega et al., 2005, PMID: 15821733). Both syndromes are characterized by mental retardation, craniofacial deformities, limb malformation, organ defects and growth retardation. SC phocomelia syndrome is described as a mild form of Roberts syndrome. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism or inheritance pattern and little difference in phenotypic variability. Therefore, the following disease entities, Roberts syndrome and SC phocomelia syndrome, have been lumped into one disease entity, Roberts-SC phocomelia syndrome (OMIM:268300). Of the 31 different variants that have been reported in patients, 16 (13 truncating, 2 splicing, and 1 missense) in 22 probands in 3 publications (Vega et al., 2005, PMID: 15821733; Schule et al., 2005, PMID:16380922; Colombo et al., 2019, PMID: 31192177) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss-of-function (LOF). This gene-disease relationship is also supported by experimental evidence (animal models, biochemical function, expression studies, and in vitro functional assays) (Whelan et al., 2012, PMID: 22101327; Percival et al., 2015, PMID: 26044958; Monnich et al., 2011, PMID: 21637801; Alomer et al., 2017, PMID: 28847955; Banerji et al., 2017, PMID: 29084713; Vega et al., 2010, PMID: 19574259; Gordillo et al., 2008, PMID: 18411254). Experimental evidence demonstrates that impairment of ESCO2 protein function is consistent with the observed phenotypes and other cohesinopathies, ESCO2 expression occurs in tissues relevant to the disease of interest and several model systems produce similar disease phenotypes, specifically impaired bone and tissue growth and impaired sister chromatid cohesion, a major diagnostic marker of Roberts-SC phocomelia syndrome. In summary, ESCO2 is definitively associated with autosomal recessive Roberts-SC phocomelia syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders Gene Curation Expert Panel on the meeting date 3.19.2021 (SOP Version 8).

From the Prenatal GCEP's secondary review on June 18th, 2024:
Prenatal phenotypes described in the literature in association with ESCO2 include prenatal growth restriction, mesomelia, oligodactyly, and cleft lip/palate (PMID: 16380922, 31192177, 34627339, 35093090, 18186147). While stillbirths have been reported in families with Roberts syndrome (PMID: 8291532), no genotyped stillbirth cases with ESCO2 variants have been reported to date. While there is one report of the occurrence of hydrops in a fetus with Roberts syndrome (PMID: 16547991), this finding has not been replicated in subsequent larger sequencing based studies, bringing this association into question.