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 affecteds-only model-free analysis and 8.2 with a reducedpenetrance 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.

PTCH1 duplication in a family with microcephaly and mild developmental delay

“…Mutations in SHH have been found in some patients with microcephaly but without HPE. 17,18 Therefore, we suggest that the gain-of-function or duplication of PTCH1 may result in microcephaly with or without HPE. We propose that patients with microcephaly or HPE of unknown origin should be screened for PTCH1 duplication.…”

Gas1 is a modifier for holoprosencephaly and genetically interacts with sonic hedgehog

“…Interestingly, the spectrum of phenotypic severity characteristic of HPE can be seen in association with identical mutations in SHH, even among members of the same pedigree (8). SHH mutation can also lead to SMMCI in the primary or secondary dentition, occurring as an isolated syndrome (12,13) or as a manifestation of HPE (14).…”

The genomic structure, chromosome location, and analysis of the human DKK1 head inducer gene as a candidate for holoprosencephaly

“…This variation was observed in three unrelated families with HPE and not in normal controls. One of these families was a large five generation family which segregated autosomal dominant HPE and is the only large family that did not show linkage to the SHH gene on human chromosome 7q36 (family 1 in Muenke et al, 1994). Interestingly, the presence or absence of the HindIII RFLP defined by this sequence alteration was correctly correlated with the disease status in 7 out of 8 available family members.…”