Gene Map Locus: 2p21
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A number sign (#) is used with this entry because of evidence that the chromosome 2 form of holoprosencephaly is due to mutations in the homeo box-containing SIX3 gene (603714).
Martin et al. (1977) described a
kindred with 7 persons affected with a syndrome manifested by cleft
lip and anterior cleft palate, hypotelorism, microcephaly, mental
retardation, scoliosis, and chronic constipation. The disorder bore
similarities to familial holoprosencephaly (see 236100).
Three of 4 affected males survived past 20 years of age. All 3
affected females died early in infancy. No affected male begot an
affected son. However, 2 presumed carrier males had an affected son.
Cantu et al. (1978) described
holoprosencephaly in 2 successive generations and suggested autosomal
dominant inheritance. Some heterozygotes had mild abnormalities of
midface development. Benke and Cohen (1983)
described a kindred ascertained through a holoprosencephalic child
and containing 6 other affected members in 3 generations. Dominant
inheritance with reduced penetrance was suggested.
Ardinger and Bartley (1988) interpreted
a family they studied as suggesting autosomal dominant inheritance.
Three individuals in 3 successive generations had severe brain
anomalies and 12 individuals had minor manifestations, mainly
microcephaly. Other findings in the family included single central
incisor (147250)
and hypotelorism, which have been suggested as mild manifestations of
autosomal dominant familial holoprosencephaly. Jaramillo
et al. (1988) described a family in which several persons had
variable combinations of craniofacial defects. The most severely
affected relatives had holoprosencephaly, while others had only mild
facial dysmorphism and decreased bitemporal diameters. One member of
the family had a single central maxillary incisor. Male-to-male
transmission occurred. Jaramillo et al.
(1988) suggested that holoprosencephaly sequence or, even better,
DeMyer sequence (DeMyer et al., 1963) is
the preferred designation.
Berry et al. (1984) and Johnson
(1989) provided information on a family in which
holoprosencephaly occurred in 3 first cousins who were offspring of
parents with single central maxillary incisor. Johnson
(1989) reported a second patient with full-blown
holoprosencephaly whose mother and sister had only single central
maxillary incisor. Johnson (1989)
suggested that holoprosencephaly is a developmental field defect of
which the mild forms can be single median incisor, hypotelorism,
bifid uvula, or pituitary deficiency. Hennekam
et al. (1991) described a family in which 1 sib had
holoprosencephaly and microcephaly, a second sib had microcephaly
alone, and the mother had microcephaly with single central maxillary
incisor, submucous cleft palate, absence of the nasal septal
cartilage, and hypotelorism.
Odent et al. (1998) reviewed 258
holoprosencephaly records involving at least 1 affected child and
found 97 cases in 79 families with nonsyndromic, nonchromosomal
holoprosencephaly. 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%.
Munke (1989) concluded that
holoprosencephaly is heterogeneous and that 5 chromosomes--2, 3, 7,
13, and 18--play major roles in causing this developmental field
defect which results from failure of the forebrain to cleave.
Abnormalities observed in several reported cases point to the
location of a causative gene on 2p, specifically 2p21 (Hecht
et al., 1991). Munke et al. (1989)
hypothesized on the basis of 3 patients with holoprosencephaly and
various interstitial deletions of the short arm of chromosome 2 that
the gene involved in early embryonic brain development is located in
band 2p21, the smallest of the 3 overlapping deletions. Grundy
et al. (1989) reported a case of synophthalmic cyclopia and
alobar holoprosencephaly associated with an interstitial deletion of
the short arm of chromosome 2: del(2)(p21p23).
Schell et al. (1996) reported the
molecular genetic characterization of 9 HPE patients with cytogenetic
deletions or translocations involving 2p21. They determined the
parental origin of the deleted chromosomes and defined the HPE2
critical region between D2S119 and D2S88/D2S391. As a first step
toward cloning the HPE2 gene which is clearly crucial for normal
brain development, they constructed a YAC contig that spans the
smallest region of deletion overlap. Several of the YACs spanned 3
different 2p21 breakpoints in HPE patients. These YACs narrowed the
HPE2 critical region to less than 1 Mb.
Wallis et al. (1999) demonstrated that the SIX3 gene (603714), which had independently been mapped to 2p, is the site of mutations causing HPE2.
Victor A. McKusick - updated : 5/27/1999
Ada Hamosh - updated : 10/29/1998
Victor A. McKusick - updated : 9/24/1998
Victor A. McKusick : 6/2/1986
carol : 5/31/1999
carol : 5/31/1999
terry : 5/27/1999
alopez : 10/29/1998
alopez : 9/29/1998
carol : 9/24/1998
terry : 7/31/1998
alopez : 6/2/1997
mark : 3/11/1996
mark : 3/7/1996
terry : 2/27/1996
mimadm : 11/6/1994
carol : 1/7/1993
carol : 12/15/1992
supermim : 3/16/1992
carol : 12/6/1991
carol : 10/17/1991