Specific mosaic KRAS mutations affecting codon 146 cause oculoectodermal syndrome and encephalocraniocutaneous lipomatosis

Oculoectodermal syndrome (OES) and encephalocraniocutaneous lipomatosis (ECCL) are rare disorders that share many common features, such as epibulbar dermoids, aplasia cutis congenita, pigmentary changes following Blaschko lines, bony tumor‐like lesions, and others. About 20 cases with OES and more t...

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Published in:	Clinical genetics Vol. 90; no. 4; pp. 334 - 342
Main Authors:	Boppudi, S., Bögershausen, N., Hove, H.B., Percin, E.F., Aslan, D., Dvorsky, R., Kayhan, G., Li, Y., Cursiefen, C., Tantcheva-Poor, I., Toft, P.B., Bartsch, O., Lissewski, C., Wieland, I., Jakubiczka, S., Wollnik, B., Ahmadian, M.R., Heindl, L.M., Zenker, M.
Format:	Journal Article
Language:	English
Published:	Oxford, UK Blackwell Publishing Ltd 01-10-2016
Subjects:	Child Child, Preschool Codon Dermoid Cyst - genetics Dermoid Cyst - pathology Ectodermal Dysplasia - genetics Ectodermal Dysplasia - pathology encephalocraniocutaneous lipomatosis Eye Diseases - genetics Eye Diseases - pathology Genetic disorders Genetic Predisposition to Disease Genotype & phenotype Humans Infant KRAS Lipomatosis - genetics Lipomatosis - pathology mosaic RASopathy Mutation Neurocutaneous Syndromes - genetics Neurocutaneous Syndromes - pathology oculoectodermal syndrome Proto-Oncogene Proteins p21(ras) - genetics somatic mutation KRAS mosaic RASopathy encephalocraniocutaneous lipomatosis somatic mutation oculoectodermal syndrome
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Summary:	Oculoectodermal syndrome (OES) and encephalocraniocutaneous lipomatosis (ECCL) are rare disorders that share many common features, such as epibulbar dermoids, aplasia cutis congenita, pigmentary changes following Blaschko lines, bony tumor‐like lesions, and others. About 20 cases with OES and more than 50 patients with ECCL have been reported. Both diseases were proposed to represent mosaic disorders, but only very recently whole‐genome sequencing has led to the identification of somatic KRAS mutations, p.Leu19Phe and p.Gly13Asp, in affected tissue from two individuals with OES. Here we report the results of molecular genetic studies in three patients with OES and one with ECCL. In all four cases, Sanger sequencing of the KRAS gene in DNA from lesional tissue detected mutations affecting codon 146 (p.Ala146Val, p.Ala146Thr) at variable levels of mosaicism. Our findings thus corroborate the evidence of OES being a mosaic RASopathy and confirm the common etiology of OES and ECCL. KRAS codon 146 mutations, as well as the previously reported OES‐associated alterations, are known oncogenic KRAS mutations with distinct functional consequences. Considering the phenotype and genotype spectrum of mosaic RASopathies, these findings suggest that the wide phenotypic variability does not only depend on the tissue distribution but also on the specific genotype.
Bibliography:	ark:/67375/WNG-Q1SDC4S9-H German Research Foundation, DFG Research Unit FOR2240 - No. HE 6743/2-1; No. HE 6743/3-1; No. RE 3777/1-1; No. CU47/6-1; No. CU47/12-1 istex:F033F314F26391A3F645A33A792BBF68647A3EA2 Fig. S1. Results of bidirectional sequencing of KRAS exon 4 in DNA samples from patients with OES and ECCL. Electropherograms show mosaic mutations in lesional tissue and absence of the mutation in DNA extracted from blood samples. Sequences are displayed in forward and reverse sequencing direction. Arrows mark the position of the mutations. German Federal Ministry of Education and Research (BMBF, NSEuroNet) ArticleID:CGE12775 German Research Foundation, DFG - No. ZE 524/10-1 ObjectType-Case Study-2 SourceType-Scholarly Journals-1 ObjectType-Feature-4 content type line 23 ObjectType-Report-1 ObjectType-Article-3 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0009-9163 1399-0004
DOI:	10.1111/cge.12775