Genotypic and phenotypic analysis of 396 individuals with mutations in Sonic Hedgehog

Benjamin D. Solomon, Kelly A. Bear, Adrian Wyllie, Amelia A. Keaton, Christele Dubourg, Veronique David, Sandra Mercier, Sylvie Odent, Ute Hehr, Aimee Paulussen, Nancy J. Clegg, Mauricio R. Delgado, Sherri J. Bale, Felicitas Lacbawan, Holly H. Ardinger, Arthur S. Aylsworth, Ntombenhle Louisa Bhengu, Stephen Braddock, Karen Brookhyser, Barbara BurtonHarald Gaspar, Art Grix, Dafne Horovitz, Erin Kanetzke, Hulya Kayserili, Dorit Lev, Sarah M. Nikkel, Mary Norton, Richard Roberts, Howard Saal, G. B. Schaefer, Adele Schneider, Erika K. Smith, Ellen Sowry, M. Anne Spence, Stavit A. Shalev, Carlos E. Steiner, Elizabeth M. Thompson, Thomas L. Winder, Joan Z. Balog, Donald W. Hadley, Nan Zhou, Daniel E. Pineda-Alvarez, Erich Roessler, Maximilian Muenke*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)473-479
Number of pages7
JournalJournal of Medical Genetics
Issue number7
StatePublished - Jul 2012
Externally publishedYes


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