Genotypic and phenotypic analysis of 396 individuals with mutations in Sonic Hedgehog.
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.
Medical Genetics Branch, National Human Genome Research Institute, NationalInstitutes of Health, Bethesda, MD, USA.
Benjamin D
BD
Solomon
Kelly A
KA
Bear
Adrian
A
Wyllie
Amelia A
AA
Keaton
Christele
C
Dubourg
Veronique
V
David
Sandra
S
Mercier
Sylvie
S
Odent
Ute
U
Hehr
Aimee
A
Paulussen
Nancy J
NJ
Clegg
Mauricio R
MR
Delgado
Sherri J
SJ
Bale
Felicitas
F
Lacbawan
Holly H
HH
Ardinger
Arthur S
AS
Aylsworth
Ntombenhle Louisa
NL
Bhengu
Stephen
S
Braddock
Karen
K
Brookhyser
Barbara
B
Burton
Harald
H
Gaspar
Art
A
Grix
Dafne
D
Horovitz
Erin
E
Kanetzke
Hulya
H
Kayserili
Dorit
D
Lev
Sarah M
SM
Nikkel
Mary
M
Norton
Richard
R
Roberts
Howard
H
Saal
G B
GB
Schaefer
Adele
A
Schneider
Erika K
EK
Smith
Ellen
E
Sowry
M Anne
MA
Spence
Stavit A
SA
Shalev
Carlos E
CE
Steiner
Elizabeth M
EM
Thompson
Thomas L
TL
Winder
Joan Z
JZ
Balog
Donald W
DW
Hadley
Nan
N
Zhou
Daniel E
DE
Pineda-Alvarez
Erich
E
Roessler
Maximilian
M
Muenke
D005260:Female; D056726:Genetic Association Studies / Q000379:methods*; D005838:Genotype; D053823:Hedgehog Proteins / Q000235:genetics* / Q000378:metabolism; D016142:Holoprosencephaly / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D016548:Prosencephalon / Q000473:pathology
D053823:Hedgehog Proteins