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Neonatal lethal Costello syndrome and unusual dinucleotide deletion/insertion mutations in HRAS predicting p.Gly12Val.

Burkitt-Wright EM, Bradley L, Shorto J, McConnell VP, Gannon C, Firth HV, Park SM, D'Amore A, Munyard PF, Turnpenny PD, Charlton A, Wilson M, Kerr B - Am. J. Med. Genet. A (2012)

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.

View Article: PubMed Central - PubMed

Affiliation: Genetic Medicine, Manchester Academic Health Science Centre, University of Manchester and Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.

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Comparison of HRAS mutations affecting codon 12 identified in Costello syndrome and in cancers. a: HRAS codon 12 mutations identified in cancers (recorded in the COSMIC database) demonstrate a high preponderance of substitutions predicting p.Gly12Val. b: HRAS codon 12 mutations in patients with CS tested in the Manchester Regional Genetics Laboratory. The p.Gly12Val mutations described in this report are shown hatched. Note the high preponderance of p.Gly12Ser mutations, with much lower numbers of other substitutions, in contrast to the mutations identified in cancers.
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fig04: Comparison of HRAS mutations affecting codon 12 identified in Costello syndrome and in cancers. a: HRAS codon 12 mutations identified in cancers (recorded in the COSMIC database) demonstrate a high preponderance of substitutions predicting p.Gly12Val. b: HRAS codon 12 mutations in patients with CS tested in the Manchester Regional Genetics Laboratory. The p.Gly12Val mutations described in this report are shown hatched. Note the high preponderance of p.Gly12Ser mutations, with much lower numbers of other substitutions, in contrast to the mutations identified in cancers.

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).


Neonatal lethal Costello syndrome and unusual dinucleotide deletion/insertion mutations in HRAS predicting p.Gly12Val.

Burkitt-Wright EM, Bradley L, Shorto J, McConnell VP, Gannon C, Firth HV, Park SM, D'Amore A, Munyard PF, Turnpenny PD, Charlton A, Wilson M, Kerr B - Am. J. Med. Genet. A (2012)

Comparison of HRAS mutations affecting codon 12 identified in Costello syndrome and in cancers. a: HRAS codon 12 mutations identified in cancers (recorded in the COSMIC database) demonstrate a high preponderance of substitutions predicting p.Gly12Val. b: HRAS codon 12 mutations in patients with CS tested in the Manchester Regional Genetics Laboratory. The p.Gly12Val mutations described in this report are shown hatched. Note the high preponderance of p.Gly12Ser mutations, with much lower numbers of other substitutions, in contrast to the mutations identified in cancers.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4495255&req=5

fig04: Comparison of HRAS mutations affecting codon 12 identified in Costello syndrome and in cancers. a: HRAS codon 12 mutations identified in cancers (recorded in the COSMIC database) demonstrate a high preponderance of substitutions predicting p.Gly12Val. b: HRAS codon 12 mutations in patients with CS tested in the Manchester Regional Genetics Laboratory. The p.Gly12Val mutations described in this report are shown hatched. Note the high preponderance of p.Gly12Ser mutations, with much lower numbers of other substitutions, in contrast to the mutations identified in cancers.
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).

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.

View Article: PubMed Central - PubMed

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