Phenotypic variability in 49 cases of ESCO2 mutations, including novel missense and codon deletion in the acetyltransferase domain, correlates with ESCO2 expression and establishes the clinical criteria for Roberts syndrome
2010
Background
Roberts syndrome(RBS) and SC
phocomeliaare caused by mutations in
ESCO2, which codes for an
acetyltransferaseinvolved in the regulation of
sister chromatidcohesion. Of 26 mutations described to date, only one missense mutation has been reported and all others are predicted to be truncating mutations. Genotype–phenotype analysis has been hampered by limited numbers of patients with clinical information available. Objective To provide unpublished clinical data for 31 patients with proven
ESCO2mutations and combine this series with previously reported clinical and mutation data on 18
cases.
MethodsGenotype–phenotype correlations and functional effects of two novel
ESCO2mutations were analysed. In situ hybridisation on human embryos at
Carnegie stages14, 17 and 21 was performed to study
ESCO2expression during development. Results and conclusions Using the cohort of 49 patients, the clinical criteria for RBS were delineated to include: growth retardation; symmetric mesomelic shortening of the limbs in which the upper limbs are more commonly and severely affected than the lower limbs; characteristic facies with
microcephaly. The severity of malformations of the facies correlates with the severity of limb reduction. The occurrence of corneal opacities may be associated with specific mutations. Two new mutations, both in the
ESCO2
acetyltransferasedomain, are described and their acetylation effects in vitro demonstrated. In situ hybridisation on human embryos showed
ESCO2expression in the brain, face, limb, kidney and gonads, which corresponds to the structures affected in RBS.
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