CYTOGENETIC REARRANGEMENTS INVOLVING THE LOSS OF THE SONIC-HEDGEHOG GENE AT 7Q36 CAUSE HOLOPROSENCEPHALY

Holoprosencephaly (HPE) is a genetically heterogeneous disorder that a ffects the midline development of the forebrain and midface in humans. As a step toward identifying one of the HPE genes, we have set out to refine the HPE3 critical region on human chromosome 7q36 by analyzing 34 cell lines from families with cytogenetic abnormalities involving 7q, 24 of which are associated with HPE. Genomic clones surrounding th e DNA marker D7S104, which has previously been shown to be in the HPE3 critical region, have been examined by fluorescent in situ hybridizat ion and microsatellite analysis of our panel of patient cell lines. We report the analysis of a cluster of four translocation breakpoints wi thin a 300-kb region of 7q36 that serves to define the minimal critica l region for HPE3 and that has directed the search for candidate genes . The human Sonic Hedgehog (hSHH) gene maps to this region and has bee n shown to be HPE3 on the basis of mutations within the coding region of the gene. We present evidence that cytogenetic deletions and/or rea rrangements of this region of chromosome 7q containing Sonic Hedgehog, and translocations that may suppress Sonic Hedgehog gene expression t hrough a position effect are common mechanisms leading to HPE.