The mutational spectrum of the Sonic Hedgehog gene in holoprosencephaly: SHH mutations cause a significant proportion of autosomal dominant holoprosencephaly. J.E. Ming¹, L. Nanni¹, M. Bocian², K.L. Jones³, R.A. Martin⁴, M.E.M. Pierpont⁴, E. Roessler⁵, M. Muenke^{1, 5}. 1) Children's Hospital of Philadelphia, Univ. of Pennsylvania School of Medicine; 2) Univ. CA Irvine; 3) Univ. CA San Diego; 4) St. Christopher's Hospital, Philadelphia, PA; Univ. of Minnesota Hospital; 5) Medical Genetics Branch, NHGRI.

   Holoprosencephaly (HPE) is a common developmental anomaly of the human forebrain and midface in which the cerebral hemispheres fail to separate into distinct left and right halves. There is a very wide spectrum of expression of the disease. We have previously reported that haploinsufficiency for Sonic Hedgehog(SHH) can cause HPE. We have now performed mutational analysis of the complete coding region and intron-exon junctions of the SHH gene in 344 affected unrelated individuals. Our analysis detected 13 additional previously unreported individuals with SHH mutations, including 2 nonsense mutations, 6 missense mutations, 4 deletions, and 1 insertion. The mutations occur throughout the coding region of the gene. No specific genotype/phenotype correlation is evident based on the type or position of the mutation. In conjunction with our previous studies, we have identified a total of 23 mutations in 344 cases of HPE. They account for 13 familial cases and 10 sporadic cases of HPE. Overall, SHH mutations were detected in 10 of 27 families (37%) showing autosomal dominant transmission of the HPE spectrum, based on structural anomalies. SHH mutations were detected in probands without a family history of HPE at a lower frequency (3.7%). Interestingly, three of the patients with a SHH mutation also had nucleotide changes in another gene that is expressed during forebrain development, raising the possibility that interactions of multiple gene products and/or environmental elements may determine the final phenotypic outcome for a given individual. We speculate that the interplay of these factors may account for the wide variability in the clinical features seen in HPE.