Roberts Syndrome via the ESCO2 Gene

Roberts syndrome (RBS; OMIM#268300), also known as Roberts-SC phocomelia syndrome (OMIM#269000), is characterized by prenatal growth retardation, limb malformations including bilateral symmetric tetraphocomelia or hypomelia caused by mesomelic shortening, and craniofacial abnormalities including bilateral cleft lip or palate, micrognathia, hypertelorism, exophthalmos, downslanting palpebral fissures, malar hypoplasia, hypoplastic nasal alae, and ear malformation. Upper limbs are more severely affected than lower limbs. Mortality is high among severely-affected pregnancies and newborns. Mildly affected individuals may survive to adulthood (Gordillo et al. GeneReviews. 2009). The diagnosis of RBS relies on cytogenetic testing, which shows the characteristic chromosomal abnormality of premature centromere separation and separation of the heterochromatic regions in most metaphase chromosomes.

Roberts Syndrome (RBS) is inherited in an autosomal recessive manner and is caused by variants in the ESCO2 gene. ESCO2 (establishment of cohesion 1 homolog 2) contains two different domains, a C-terminal portion with acetyltransferase activity and an N-terminal portion that binds to chromatin (Vega et al. Nat Genet 37:468-470, 2005). The acetyltransferase domain is proposed to play an important role in establishing sister chromatid cohesion during S phase after DNA replication (Williams et al. Curr Biol 3:2025-2036, 2003). The majority of variants in ESCO2 are frameshift or nonsense variants that lead to protein truncation or nonsense-mediated decay, which suggests that the molecular mechanism underlying RBS involves loss of acetyltransferase activity. The rare missense variants in this gene lead to highly conserved amino acid substitutions in the acetyltransferase domain and cause loss of acetyltransferase activity equivalent to that produced by truncating variants (Gordillo et al. Hum Mol Genet 17:2172–2180, 2008; Vega et al. J Med Genet 47:30-37, 2010).

To date, all individuals with a cytogenetic diagnosis of RBS have had variants in ESCO2 (Gordillo et al. 2009).

This test provides full coverage of all coding exons of the ESCO2 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).