Gene Map Locus: 7q36
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A number sign (#) is used with this entry because of evidence that the disorder is caused by mutation in the gene encoding the human sonic hedgehog homolog (600725).
A form of holoprosencephaly that appears to be associated with a chromosomal aberration in the 7q36 region has rather arbitrarily been designated holoprosencephaly type 3. Its relationship, if any, to entities discussed in entries 157170 and 236100 is unclear.
Lurie et al. (1990) pointed out that at
least 9 cases of HPE have occurred in patients with confirmed loss of
7q34-q36. They reported balanced rearrangements involving 7q in 2
mothers examined after the birth of their nonkaryotyped infants with
HPE and hydronephrosis. They suggested that in both infants del(7q)
was the most probable cause of HPE. Cyclopia and cebocephaly were
conspicuous features in the cases of del(7q). Sporadic cases of
cyclopia have been observed in association with trisomy 13, ring 13,
and other chromosomal abnormalities and many have had normal
karyotypes. Masuno and Orii (1990) also
pointed to reports of holoprosencephaly in association with terminal
7q deletion. Kleczkowska et al. (1990)
described the case of a female fetus with hemilobar holoprosencephaly
and 46,XX,der(7)t(7;8)(q36.1;p12)mat karyotype. The holoprosencephaly
sequence was considered to be related to the distal 7(q36.1-qter)
deficiency. Hatziioannou et al. (1991)
reviewed the evidence suggesting that a locus for holoprosencephaly
resides at or near 7q36. Gurrieri et al.
(1993) characterized the 7q deletions in 13 HPE patients and
constructed a high resolution physical map of 7q32-qter. As a first
step toward cloning an HPE gene crucial for normal brain development,
they defined the HPE minimal critical region in 7q36 between D7S292
and D7S392. They pictured 1 of the patients with the characteristic
facies of the severe form of HPE which included a single fused eye
(cyclopia) and a nose-like structure (proboscis) above the eye.
Midline structures of the forebrain were absent, consistent with
alobar HPE.
Muenke et al. (1993) performed linkage
studies in 10 families with autosomal dominant HPE. The phenotypic
features in affected individuals varied from the most severe forms
with single brain ventricle and cyclopia to milder forms with ocular
hypotelorism and midface hypoplasia to clinically unaffected
carriers. Under the most conservative model-free analysis, linkage
between HPE and D7S22 showed a combined lod score of 7.2 at theta =
0.0, with 1 family independently presenting a lod score of 3.0 at
theta = 0.0. Muenke et al. (1993) concluded
that autosomal dominant HPE is at the locus that has been designated
HPE3 and mapped to 7q36. Muenke et al.
(1994) suggested that mutations in the HPE3 gene are responsible
for both sporadic HPE and a majority of families with autosomal
dominant HPE. Clinical evaluation of the affected individuals in the
9 families in the report of Muenke et al.
(1994) confirmed the previously reported phenotypic variability
of autosomal dominant HPE. In each family, one or more obligate gene
carriers had classic (alobar, semilobar, or lobar) HPE, many of whom
died during early infancy. Others had HPE microforms such as
microcephaly, mental retardation, microphthalmia, ocular coloboma,
ocular hypotelorism, midface hypoplasia, single central upper
incisor, cleft lip, and cleft lip and palate. Some obligate gene
carriers had normal phenotypes, including normal intellect. In 1 of
the 9 families, linkage to D7S22 and other markers on chromosome 7q
was excluded, thus indicating genetic heterogeneity. The clinical
manifestations, including the HPE microforms, did not differ between
individuals in the unlinked kindred and those in the other 8 kindreds
linked to 7q36.
Belloni et al. (1996) refined the
position of HPE3 by detailed characterization of HPE3 patients with
rearrangements involving chromosome 7q36. They also established a
contig of genomic clones in this region. Belloni
et al. (1996) demonstrated that a cDNA for SHH (600725),
the human sonic hedgehog homolog, showed specific hybridization to
the contig which spanned the translocation breakpoint. Further
analysis revealed that SHH mapped approximately 250 and 15 kb
centromeric of T1 and T2, respectively (T1 and T2 represent the
translocation breakpoints in 2 unrelated patients with a mild form of
HPE3). Belloni et al. (1996) proposed that
the chromosomal rearrangements remove distal cis-acting regulatory
elements or exert long-range position effects causing aberrant
expression of the gene. They noted that HPE patients exhibiting
deletions of the SHH region are generally more severely affected than
are the translocation patients. The mild HPE phenotype displayed by
the patient with the T2 balanced translocation included premaxillary
aplasia with midline cleft lip, hypotelorism, sensorineural hearing
loss, lack of tooth eruption, and cervical cord compression due to
stenosis. Benzacken et al. (1997) reported
4 new cases of holoprosencephaly in fetuses with abnormal karyotypes.
Three of these had terminal deletions of 7q, confirming the
importance of 7q36 in holoprosencephaly. The fourth fetus had an
apparently balanced de novo translocation, t(7;13)(q21.2;q33),
without any visible loss of the distal part of chromosome 7q.
Benzacken et al. (1997) proposed either a
long range positional effect or the existence of genes involved in
prosencephalon development at 7q21.2 or 13q33 as an explanation for
this.
Roessler et al. (1996) identified SHH
as the gene responsible for HPE3. They analyzed 30 autosomal dominant
HPE families and found 5 families that segregated different
heterozygous SHH mutations. Two of these mutations predict premature
termination of SHH protein (600725.0002
and 600725.0003).
The remaining 3 mutations altered highly conserved residues in the
vicinity of the alpha helix-1 motif (600725.0004
and 600725.0005)
or the signal cleavage site (600725.0001).
Roessler et al. (1996) noted that in
humans loss of one SHH allele is sufficient to cause HPE, whereas in
the mouse both alleles need to be lost to produce a similar CNS
phenotype. They observed that haploinsufficiency for SHH in human is
sufficient to disturb ventral midline neurogenesis but is
insufficient to cause ventralization defects of sclerotome or limb
abnormalities.
Odent et al. (1998) reviewed 258 HPE
records involving at least 1 affected child and found 97 cases in 79
families with nonsyndromic, nonchromosomal HPE. A high degree of
familial aggregation was found in 29% of families. By segregation
analysis, Odent et al. (1998) concluded
that autosomal dominant inheritance with incomplete penetrance (82%
for major and 88% for major and minor) was the most likely mode of
inheritance. Sporadic cases accounted for 68%, and the recurrence
risk after an isolated case was predicted to be 13 to 14%.
Ada Hamosh - updated : 10/29/1998
Michael J. Wright - updated : 6/16/1998
Moyra Smith - updated : 11/4/1996
Victor A. McKusick : 12/6/1991
alopez : 10/29/1998
carol : 9/24/1998
terry : 6/16/1998
mark : 11/5/1996
mark : 11/4/1996
carol : 7/25/1996
mimadm : 9/24/1994
carol : 9/9/1994
carol : 9/29/1993
carol : 3/22/1993
carol : 12/15/1992
supermim : 3/16/1992