LINKAGE OF A HUMAN BRAIN MALFORMATION, FAMILIAL HOLOPROSENCEPHALY, TOCHROMOSOME-7 AND EVIDENCE FOR GENETIC-HETEROGENEITY

Holoprosencephaly (HPE) is a common malformation of the developing for ebrain and midface character ized by incomplete penetrance and variabl e expressivity. Familial HPE has been reported in many families with a utosomal dominant inheritance in some and apparent autosomal recessive inheritance in others. We have examined 125 individuals from nine fam ilies with autosomal dominant HPE. Expression in gene carriers varied from alobar HPE and cyclopia through microforms such as microcephaly o r single central incisor to normal phenotype. We performed linkage stu dies by either Southern blot or polymerase chain reaction analyses wit h DNA markers (D7S22, D7S550, and D7S483) that are deleted from some p atients with sporadic HPE and flank a translocation breakpoint in 7q36 associated with HPE. The strongest support for linkage was with D7S22 , which was linked with no recombination to autosomal dominant HPE in eight of nine families with a combined logarithm of odds score of 6.4 with an affecteds-only model-free analysis and 8.2 with a reduced-pene trance model and all phenotypes. Close linkage to this region could be excluded in one family, and there was significant evidence of genetic heterogeneity. These results show that a gene for autosomal dominant HPE is located in a chromosomal region (7q36) known to be involved in sporadic HPE with visible cytogenetic deletions. They also demonstrate genetic heterogeneity in familial HPE. We hypothesize that mutations of a gene in 7q36, designated HPE3, are responsible for both sporadic HPE and a majority of families with autosomal dominant HPE.