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Type: Artigo de periódico
Title: Genotypic and phenotypic analysis of 396 individuals with mutations in Sonic Hedgehog
Author: Solomon, Benjamin D.
Bear, Kelly A.
Wyllie, Adrian
Keaton, Amelia A.
Dubourg, Christele
David, Veronique
Mercier, Sandra
Odent, Sylvie
Hehr, Ute
Paulussen, Aimee
Clegg, Nancy J.
Delgado, Mauricio R.
Bale, Sherri J.
Lacbawan, Felicitas
Ardinger, Holly H.
Aylsworth, Arthur S.
Bhengu, Ntombenhle Louisa
Braddock, Stephen
Brookhyser, Karen
Burton, Barbara
Gaspar, Harald
Grix, Art
Horovitz, Dafne
Kanetzke, Erin
Kayserili, Hulya
Lev, Dorit
Nikkel, Sarah M.
Norton, Mary
Roberts, Richard
Saal, Howard
Schaefer, G. B.
Schneider, Adele
Smith, Erika K.
Sowry, Ellen
Spence, M. Anne
Shalev, Stavit A.
Steiner, Carlos E.
Thompson, Elizabeth M.
Winder, Thomas L.
Balog, Joan Z.
Hadley, Donald W.
Zhou, Nan
Pineda-Alvarez, Daniel E.
Roessler, Erich
Muenke, Maximilian
Abstract: Background Holoprosencephaly (HPE), the most common malformation of the human forebrain, may result from mutations in over 12 genes. Sonic Hedgehog (SHH) was the first such gene discovered; mutations in SHH remain the most common cause of nonchromosomal HPE. The severity spectrum is wide, ranging from incompatibility with extrauterine life to isolated midline facial differences. Objective To characterise genetic and clinical findings in individuals with SHH mutations. Methods Through the National Institutes of Health and collaborating centres, DNA from approximately 2000 individuals with HPE spectrum disorders were analysed for SHH variations. Clinical details were examined and combined with published cases. Results This study describes 396 individuals, representing 157 unrelated kindreds, with SHH mutations; 141 (36%) have not been previously reported. SHH mutations more commonly resulted in non-HPE (64%) than frank HPE (36%), and non-HPE was significantly more common in patients with SHH than in those with mutations in the other common HPE related genes (p<0.0001 compared to ZIC2 or SIX3). Individuals with truncating mutations were significantly more likely to have frank HPE than those with non-truncating mutations (49% vs 35%, respectively; p=0.012). While mutations were significantly more common in the N-terminus than in the C-terminus (including accounting for the relative size of the coding regions, p=0.00010), no specific genotype. phenotype correlations could be established regarding mutation location. Conclusions SHH mutations overall result in milder disease than mutations in other common HPE related genes. HPE is more frequent in individuals with truncating mutations, but clinical predictions at the individual level remain elusive.
Editor: B M J Publishing Group
Citation: Journal of Medical Genetics. B M J Publishing Group, v.49, n.7, p.473-479, 2012
Rights: fechado
Identifier DOI: 10.1136/jmedgenet-2012-101008
Date Issue: 2012
Appears in Collections:FCM - Artigos e Outros Documentos

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