RT Journal Article
SR Electronic
T1 Genotypic and phenotypic analysis of 396 individuals with mutations in <em>Sonic Hedgehog</em>
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 473
OP 479
DO 10.1136/jmedgenet-2012-101008
VO 49
IS 7
A1 Solomon, Benjamin D
A1 Bear, Kelly A
A1 Wyllie, Adrian
A1 Keaton, Amelia A
A1 Dubourg, Christele
A1 David, Veronique
A1 Mercier, Sandra
A1 Odent, Sylvie
A1 Hehr, Ute
A1 Paulussen, Aimee
A1 Clegg, Nancy J
A1 Delgado, Mauricio R
A1 Bale, Sherri J
A1 Lacbawan, Felicitas
A1 Ardinger, Holly H
A1 Aylsworth, Arthur S
A1 Bhengu, Ntombenhle Louisa
A1 Braddock, Stephen
A1 Brookhyser, Karen
A1 Burton, Barbara
A1 Gaspar, Harald
A1 Grix, Art
A1 Horovitz, Dafne
A1 Kanetzke, Erin
A1 Kayserili, Hulya
A1 Lev, Dorit
A1 Nikkel, Sarah M
A1 Norton, Mary
A1 Roberts, Richard
A1 Saal, Howard
A1 Schaefer, G B
A1 Schneider, Adele
A1 Smith, Erika K
A1 Sowry, Ellen
A1 Spence, M Anne
A1 Shalev, Stavit A
A1 Steiner, Carlos E
A1 Thompson, Elizabeth M
A1 Winder, Thomas L
A1 Balog, Joan Z
A1 Hadley, Donald W
A1 Zhou, Nan
A1 Pineda-Alvarez, Daniel E
A1 Roessler, Erich
A1 Muenke, Maximilian
YR 2012
UL http://jmg.bmj.com/content/49/7/473.abstract
AB 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&lt;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.