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GENOTYPIC AND PHENOTYPIC ANALYSIS OF 396 INDIVIDUALS WITH MUTATIONS IN SONIC HEDGEHOG
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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;
p¼0.012). 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, p¼0.00010), 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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