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

Benjamin D. Solomon 1 Kelly A. Bear 1, 2 Adrian Wyllie 1 Amelia A. Keaton 1 Christele Dubourg 3 Véronique David 3 Sandra Mercier 3, 4 Sylvie Odent 3 Ute Hehr 5 Aimee Paulussen 6 Nancy J. Clegg 7 Mauricio R. Delgado 7 Sherri Bale 8 Felicitas Lacbawan 9 Holly H. Ardinger 10 Arthur S. Aylsworth 11 Ntombenhle Louisa Bhengu 12 Stephen Braddock 13 Karen Brookhyser 14 Barbara Burton 15, 16 Harald Gaspar 17 Art Grix 14 Dafne Horovitz 18 Erin Kanetzke 13 Hulya Kayserili 19 Dorit Lev 20 Sarah M. Nikkel 21 Mary Norton 22 Richard Roberts 23 Howard Saal 24 Bradley G. Schaefer 25 Adele Schneider 26 Erika K. Smith 21 Ellen Sowry 27 Anne M. Spence 28 Stavit A. Shalev 29, 30 Carlos E. Steiner 31 Elizabeth M. Thompson 32 Thomas L. Winder 33 Joan Z. Balog 1 Donald W. Hadley 1 Nan Zhou 1 Daniel E. Pineda-Alvarez 1 Erich Roessler 1 Maximilian Muenke 1, * 
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 non-chromosomal 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.
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Contributor : Hervé De Villemeur Connect in order to contact the contributor
Submitted on : Monday, July 16, 2012 - 1:00:23 PM
Last modification on : Wednesday, March 30, 2022 - 2:34:47 PM

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Benjamin D. Solomon, Kelly A. Bear, Adrian Wyllie, Amelia A. Keaton, Christele Dubourg, et al.. Genotypic and phenotypic analysis of 396 individuals with mutations in Sonic Hedgehog.. Journal of Medical Genetics, BMJ Publishing Group, 2012, 49 (7), pp.473-9. ⟨10.1136/jmedgenet-2012-101008⟩. ⟨inserm-00718148⟩



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