Solomon, Benjamin D. and Bear, Kelly A. and Wyllie, Adrian and Keaton, Amelia A. and Dubourg, Christele and David, Veronique and Mercier, Sandra and Odent, Sylvie and Hehr, Ute and Paulussen, Aimee and Clegg, Nancy J. and Delgado, Mauricio R. and Bale, Sherri J. and Lacbawan, Felicitas and Ardinger, Holly H. and Aylsworth, Arthur S. and Bhengu, Ntombenhle Louisa and Braddock, Stephen and Brookhyser, Karen and Burton, Barbara and Gaspar, Harald and Grix, Art and Horovitz, Dafne and Kanetzke, Erin and Kayserili, Hulya and Lev, Dorit and Nikkel, Sarah M. and Norton, Mary and Roberts, Richard and Saal, Howard and Schaefer, G. B. and Schneider, Adele and Smith, Erika K. and Sowry, Ellen and Spence, M. Anne and Shalev, Stavit A. and Steiner, Carlos E. and Thompson, Elizabeth M. and Winder, Thomas L. and Balog, Joan Z. and Hadley, Donald W. and Zhou, Nan and Pineda-Alvarez, Daniel E. and Roessler, Erich and Muenke, Maximilian (2012) Genotypic and phenotypic analysis of 396 individuals with mutations in Sonic Hedgehog. JOURNAL OF MEDICAL GENETICS, 49 (7). pp. 473-479. ISSN 0022-2593,
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | HOLOPROSENCEPHALY-LIKE PHENOTYPE; GENE; ZIC2; FREQUENCY; SPECTRUM; FAMILY; SIX3; SHH; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Humangenetik |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 11 May 2020 11:14 |
| Last Modified: | 11 May 2020 11:14 |
| URI: | https://pred.uni-regensburg.de/id/eprint/18498 |
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