The mutational spectrum of the Sonic Hedgehog gene in holoprosencephaly: SHH mutations cause a significant proportion of autosomal dominant holoprosencephaly

Holoprosencephaly (HPE) is a common developmental anomaly of the human fore brain and midface where the cerebral hemispheres fail to separate into dist inct left and right halves. We have previously reported haploinsufficiency for Sonic Hedgehog (SHH) as a cause for HPE. We have now performed mutation al analysis of the complete coding region and intron-exon junctions of the SHH gene in 344 unrelated affected individuals. Herein, we describe 13 addi tional unrelated affected individuals with SHH mutations, including nonsens e and missense mutations, deletions and an insertion. These mutations occur throughout the extent of the gene. No specific genotype-phenotype associat ion is evident based on the correlation of the type or position of the muta tions. In conjunction with our previous studies, we have identified a total of 23 mutations in 344 unrelated cases of HPE, They account for 14 cases o f familial HPE and nine cases of sporadic HPE. Mutations in SHH were detect ed in 10 of 27 (37%) families showing autosomal dominant transmission of th e HPE spectrum, based on structural anomalies. Interestingly, three of the patients with an SHH mutation also had abnormalities in another gene that i s expressed during forebrain development. We suggest that the interactions of multiple gene products and/or environmental elements may determine the f inal phenotypic outcome for a given individual and that variations among th ese factors: may cause the wide variability in the clinical features seen i n HPE.