Neonatal lethal Costello syndrome and unusual dinucleotide deletion/insertion mutations in HRAS predicting p.Gly12Val.
Bottom Line: Dysmorphism was subtle or non-specific, with edema, coarsened facial features, prominent forehead, depressed nasal bridge, anteverted nares, and low-set ears.Proximal upper limb shortening, a small bell-shaped chest, talipes, and fixed flexion deformities of the wrists were seen.Clinical management should be informed by knowledge of the poor prognosis of this condition.
Affiliation: Genetic Medicine, Manchester Academic Health Science Centre, University of Manchester and Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.Show MeSH
Related in: MedlinePlus
Mentions: The preponderance of dinucleotide deletion/insertion mutations identified in this series is remarkable, as such mutations are exceedingly rare both in other germline disorders and also in cases of somatic mutation, such as those that occur in cancer. The COSMIC database of somatic alterations in cancer (http://www.sanger.ac.uk/perl/genetics/CGP/cosmic), as of 6th October 2011, included 749 HRAS mutations, identified in 21,905 tumor samples tested. Of these, 453 affected codon 12. These are shown in Figure 4, and of note none were dinucleotide deletion/insertions. Similar mutations have, however, been very rarely identified affecting codon 61 of HRAS (in 6/21905 tumor samples), and also with extreme rarity in other RAS genes in cancers, for example 54 such mutations altering codon 12 of KRAS have been included in COSMIC, in comparison to 17,490 point mutations altering this codon (in a total of 92,270 tumor samples included at October 6, 2011).
Affiliation: Genetic Medicine, Manchester Academic Health Science Centre, University of Manchester and Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.