title: Linkage of a human brain malformation, familial holoprosencephaly, to chromosome 7 and evidence for genetic heterogeneity.
abstract: Holoprosencephaly (HPE) is a common malformation of the developing forebrain and midface characterized by incomplete penetrance and variable expressivity. Familial HPE has been reported in many families with autosomal dominant inheritance in some and apparent autosomal recessive inheritance in others. We have examined 125 individuals from nine families with autosomal dominant HPE. Expression in gene carriers varied from alobar HPE and cyclopia through microforms such as microcephaly or single central incisor to normal phenotype. We performed linkage studies by either Southern blot or polymerase chain reaction analyses with DNA markers (D7S22, D7S550, and D7S483) that are deleted from some patients 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 affected-only model-free analysis and 8.2 with a reduced-penetrance 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.
authors.affiliation: Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia 19104.
authors.forename: M
authors.initials: M
authors.lastname: Muenke
authors.forename: F
authors.initials: F
authors.lastname: Gurrieri
authors.forename: C
authors.initials: C
authors.lastname: Bay
authors.forename: D H
authors.initials: DH
authors.lastname: Yi
authors.forename: A L
authors.initials: AL
authors.lastname: Collins
authors.forename: V P
authors.initials: VP
authors.lastname: Johnson
authors.forename: R C
authors.initials: RC
authors.lastname: Hennekam
authors.forename: G B
authors.initials: GB
authors.lastname: Schaefer
authors.forename: L
authors.initials: L
authors.lastname: Weik
authors.forename: M S
authors.initials: MS
authors.lastname: Lubinsky
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015139:Blotting, Southern; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D002897:Chromosomes, Human, Pair 7; D004247:DNA / Q000097:blood / Q000235:genetics / Q000302:isolation & purification; D005260:Female; D005799:Genes, Dominant; D008040:Genetic Linkage; D005819:Genetic Markers; D016142:Holoprosencephaly / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction
chemical_list: D005819:Genetic Markers; D004247:DNA