*119530 OROFACIAL CLEFT 1; OFC1
Alternative
titles; symbols
CLEFT LIP WITH OR WITHOUT CLEFT PALATE
OROFACIAL CLEFT, NONSYNDROMIC; OFC
table OF
CONTENTS
Database Links
Gene Map Locus: 6p24.3
Note: pressing the 
symbol will find the citations in MEDLINE whose
text most closely matches the text of the preceding
OMIM paragraph, using the Entrez MEDLINE
neighboring function.
TEXT
Over 200 syndromes, including a number that are
either chromosomal or mendelian in causation, have
cleft lip and/or palate as feature(s) (Gorlin,
1982). As precise a diagnosis as possible is
necessary before falling back on empiric risk
figures for genetic counseling. It is clear from
family studies that isolated cleft palate
(119540)
is genetically distinct from cleft lip with or
without cleft palate (CL/P). CL/P appears to have
complex genetics. Curtis et
al. (1961) estimated that the risk of
recurrence in subsequently born children is 4% if
one child has it, 4% if one parent has it, 17% if
one parent and one child have it, and 9% if two
children have it. The syndrome of cleft lip with or
without cleft palate in association with mucous
pits of the lower lip is inherited as an autosomal
dominant (119300).
Carter et al. (1982)
followed up on the families of cases of CL/P
operated on at The Hospital for Sick Children
('Great Ormond St.'), London, between 1920 and
1939, to obtain information on the proportion
affected of children and grandchildren. The
probands were those who had survived, were
successfully traced, and found to have had at least
1 child. Patients of the 1920-1939 period traced
through a child, either normal or affected, were
excluded, as were patients with recognized
syndromes. The proportion affected of children of
probands was 3.15%, of sibs 2.79%, and of parents
1.18%. The lower proportion of parents affected was
attributed to reduced reproductive fitness of
patients born 2 generations ago. The proportion
affected of nephews and nieces, aunts and uncles,
and grandchildren was 0.47%, 0.59% and 0.8%,
respectively. The proportion affected of first
cousins was 0.27%. The birth frequency in England
was estimated to be about 0.1%. The proportion of
sibs affected increased with increasing severity of
the malformation in the proband, when the proband
was female, and when the proband had an affected
parent or already had 1 affected sib. Carter
et al. (1982) concluded that the most
economical explanation of the findings is the
multifactorial threshold model and that a single
mutant gene in unlikely. Chung
et al. (1986) analyzed the genetics of CL/P on
a comparative basis, in the Danish (Bixler
et al., 1971; Melnick et
al., 1980) and Japanese (Koguchi,
1975) data. Japanese are known to have a higher
population incidence of CL/P and yet a lower
recurrence risk among relatives than is true in
Caucasian populations. Chung
et al. (1986) concluded that the Danish data is
best explained by a combination of major gene
action and multifactorial inheritance. The major
gene was thought to be recessive with a frequency
of 0.035. Heritability was estimated as 0.97. On
the contrary, the Japanese data could best be
accounted for only by multifactorial inheritance
with the heritability estimate of 0.77. Following
previous studies suggesting that symmetry for
certain bilaterally represented features may be an
indicator of genetic predisposition to CL/P,
Crawford and Sofaer
(1987) devised an asymmetry score which
correctly classified 85% of familial cleft patients
and unrelated noncleft controls. Applying the same
stepwise logistic regression to sporadic cases, 26%
fell into the range occupied by the majority of
familial patients, suggesting that these had a high
level of genetic predisposition. In West Bengal,
India, Ray et al. (1993)
ascertained 90 extended families having one or more
individuals affected with CL/P. They concluded that
the hypothesis of major-locus inheritance alone
could not be rejected. Among major-locus models
examined, strictly recessive inheritance was
rejected, but codominant and dominant models were
not. Neither the addition of a multifactorial
component nor the addition of a proportion of
sporadic cases to the major-locus model improved
the fit of the data.
Ardinger et al. (1989)
observed a significant association between 2 RFLPs
at the transforming growth factor alpha (190170)
locus and the occurrence of clefting. The authors
suggested that either the TGFA gene or DNA
sequences adjacent to the locus contribute to the
development of some cases of cleft lip with or
without cleft palate in humans. However, in a study
of 7 families with CL/P segregating in a dominant
manner, the TGFA haplotype associations reported by
Ardinger et al. (1989)
were not seen, and in 1 family clefting did not
cosegregate with TGFA, thus ruling out tight
linkage (Hecht et al., 1990,
1991). On the other
hand, Chenevix-Trench et al.
(1991) confirmed the existence of an excess
frequency of the same TaqI allele found by
Ardinger et al. (1989).
Vintiner et al. (1992)
studied 8 families with cleft lip with or without
cleft palate inherited in an apparently autosomal
dominant manner and excluded linkage with TGFA. In
a study of 3 RFLPs at the TGFA locus in 60
unrelated British Caucasian subjects with
nonsyndromic CL/P and 60 controls, Holder
et al. (1992) found a highly significant
association between the TaqI RFLP and the
occurrence of clefting, and no significant
association with the other 2 RFLPs. Chenevix-Trench
et al. (1992) extended their analysis of the
TGFA TaqI RFLP to 2 other TGFA RFLPs and 7 other
RFLPs at 5 candidate genes. Significant
associations with the TGFA TaqI and BamHI RFLPs
were confirmed. Of particular interest, in view of
the known teratogenic role of retinoic acid, was a
significant association with a PstI RFLP of RARA
(180240)
(P = 0.016, not corrected for multiple testing).
The effect on risk of the A2 allele appeared to be
additive; although the A2A2 homozygote only has an
odds ratio of about 2 and recurrence risk to
first-degree relatives of 1.06, because it is so
common, it may account for as much as a third of
the attributable risk of clefting. There was no
evidence of interaction between the TGFA and RARA
polymorphisms on risk, but jointly they appeared to
account for almost half the attributable risk of
clefting. Sassani et al.
(1993) and Shiang et al.
(1993) likewise found a significant association
between TGFA alleles and CL/P. Sequence analysis of
the variants disclosed a cluster of 3 variable
sites within 30 bp of each other in the 3-prime
untranslated region previously associated with an
antisense transcript in the TGFA gene (Shiang
et al., 1993). Farrall
et al. (1993) attempted to resolve the apparent
paradox concerning the role of TGFA in CL/P: the
very strong support from population-based studies
for TGFA as a susceptibility locus but the seeming
exclusion of TGFA as a candidate locus by linkage
studies in a series of multiplex CL/P families
(Hecht et al., 1991).
Studies to determine whether women who smoke
during early pregnancy are at increased risk of
delivering infants with orofacial clefts have
yielded conflicting results. In part, the
inconclusive or contradictory findings result from
inadequate study design. Using a large
population-based case-control study, Shaw
et al. (1996) investigated whether parental
peri-conceptional cigarette smoking was associated
with an increased risk for having offspring with
orofacial clefts. They also investigated the
influence of genetic variation at the TGFA locus on
the relation between smoking and clefting. They
found that risks associated with maternal smoking
were most elevated for isolated CL/P and for
isolated cleft palate when mothers smoked 20 or
more cigarettes per day. Analyses controlling for
the potential influence of other variables did not
reveal substantially different results. Clefting
risks were even greater for infants with the TGFA
allele previously associated with clefting when the
mothers smoked 20 or more cigarettes per day. These
risks for white infants ranged from 3-fold to
11-fold across phenotypic groups. Paternal smoking
was not associated with clefting among the
offspring of nonsmoking mothers, and passive smoke
exposures were associated with at most slightly
increased risks. Shaw et al.
(1996) concluded that this is an example of
gene-environment interaction in the occurrence of
orofacial clefting.
Mitchell (1996)
analyzed published data on the association between
nonsyndromic CL/P and genetic variation at the TGFA
locus. She found evidence of significant
heterogeneity in the TGFA allele frequencies
between cases, but not controls, from different
studies. Because of difficulties in identifying the
source(s) of the observed heterogeneity, the
evidence regarding an association remained
inconclusive, in the opinion of Mitchell
(1996).
Eiberg et al. (1987)
selected 58 pedigrees with nonsyndromic orofacial
cleft from among a comprehensive collection of
Danish cases for suggestiveness of autosomal
dominant inheritance. Linkage with 42 non-DNA
polymorphic marker systems was investigated. Both
CL/P and cleft palate only (CPO) were, for the
purpose of linkage analysis, scored as if being due
to an autosomal dominant gene with complete
penetrance. Linkage was found with clotting factor
XIIIA (134570);
for males alone, the maximal lod score was 3.40 at
theta = 0.00; for females alone, 0.30 at theta =
0.21; and for these combined, 3.66 at theta = 0.00
for males, and theta = 0.26 for females. The
findings were taken to suggest that since F13A is
located on the distal portion of 6p, a major locus
for nonsyndromic orofacial cleft is also located in
this region. Since both cleft lip with or without
cleft palate and isolated cleft palate pedigrees
contributed to the positive score, it is possible
that the locus on 6p carries 2 cleft alleles. In a
study of 12 autosomal dominant families with
nonsyndromic cleft lip with or without cleft
palate, Hecht et al.
(1993) excluded linkage with HLA and F13A.
Multipoint analysis showed no evidence of a
clefting locus in a region spanning 54 cM on 6p in
these CL/P families.
Using 13 microsatellite markers specific for 4q
in a study of 7 of 8 persons with CL/P in a
5-generation family, Beiraghi
et al. (1994) found evidence of linkage between
the phenotype and 2 markers, D4S175 (maximum lod =
2.27 at theta = 0) and D4S192 (maximum lod = 1.93
at theta = 0). No linkage with markers on
chromosome 6 was found in this family.
Temple et al. (1989)
described cleft lip and palate in 3 generations of
each of 2 families; in 1 family, there was an
instance of male-to-male transmission. Hecht
(1990) presented the pedigrees of 11 families
with multigenerational involvement of cleft lip and
palate. One family had affected persons in 3
successive generations. Hecht
et al. (1991) performed complex segregation
analysis of nonsyndromic CL/P in 79 families
ascertained through a proband diagnosed at the Mayo
clinic. In one analysis, the dominant or codominant
mendelian major locus models of inheritance
provided the most parsimonious fit. In another, the
multifactorial threshold model and the mixed model
were also consistent with the data. However, the
high heritability (0.93) in the multifactorial
threshold model suggested that any random exogenous
factors were unlikely to be the underlying
mechanism, and the mixed model indicated that this
high heritability was accounted for by a major
dominant locus component. Thus, the best
explanation for the findings of the study was a
putative major locus associated with markedly
decreased penetrance. In a reanalysis of recurrence
patterns from several family studies of CL/P,
Mitchell and Risch
(1992) found that the recurrence patterns in
first-degree relatives were compatible with
expectations for either a multifactorial threshold
trait or a generalized (precise mode of inheritance
unspecified) single major locus trait. The use of
multiple thresholds based on proband sex, defect
bilaterality, or palate involvement did not help to
discriminate between these models. They concluded,
however, that the pattern of recurrence among MZ
twins and more remote relatives is not consistent
with the single-major-locus inheritance but is
compatible with either a multifactorial threshold
model or a model specifying multiple interacting
loci. For such a model, no single locus could
account for more than a 6-fold increase in risk to
first-degree relatives. Between 1980 and 1987 in
Shanghai, the birth incidence of nonsyndromic CL/P
was 1.11/1,000, with a male/female ratio of 1.42
(Marazita et al., 1992).
Marazita et al. (1992)
analyzed family data from almost 2,000 probands
ascertained from among individuals operated on
during the years 1956-1983 at surgical hospitals in
Shanghai. They rejected the hypothesis of no
familial transmission and of multifactorial
inheritance alone. Of the major locus models, the
autosomal recessive was significantly more likely.
They concluded that the best-fitting, most
parsimonious model for CL/P in Shanghai is that of
an autosomal recessive major locus. By linkage
studies, Hecht et al.
(1992) excluded the region of chromosome 1q
which carries the lip-pit syndrome (van der Woude
syndrome; VWS; 119300)
as the site of the mutation in this disorder and in
isolated cleft palate.
Several studies had demonstrated an association
between facial shape in parents and the presence of
oral clefts in their offspring. It was assumed that
facial shape was one predisposing component among
many in a multifactorial model of inheritance. By
cephalometric analysis of a large family with 5
generations of affected individuals, Ward
et al. (1994) concluded that facial shape can
be used to identify presumed carriers of a major
gene associated with an increased risk for oral
clefts. Discriminant function analysis indicated
that at-risk individuals could be recognized
through a combination of increased midfacial and
nasal cavity widths, reduced facial height, and a
flat facial profile. The use of this approach in
providing critical information needed in the search
for molecular markers that segregate with the
genetic risk for clefting was emphasized.
Davies et al. (1995)
used YAC clones from contigs in 6p25-p23 to
investigate 3 unrelated patients with cleft
lip/palate who showed abnormalities of 6p. Case 1
had bilateral cleft lip and palate, and a balanced
translocation reported as 46,XY,t(6,7)(p23;q36.1).
Case 2 had multiple anomalies, including cleft lip
and palate and was reported as
46,XX,del(6)(p23;pter). Case 3 had bilateral cleft
lip and palate and carried a balanced translocation
reported as t(6;9)(p23;q22.3). Davies
et al. (1995) identified 2 YAC clones, both of
which crossed the breakpoint in cases 1 and 3 and
were deleted in case 2. These clones mapped to
6p24.3 and, therefore, suggested the presence of a
locus for orofacial clefting in that region.
It is noteworthy that there is some homology of
synteny between human 6p and mouse chromosome 13.
Furthermore, Wakasugi et al.
(1988) demonstrated an autosomal dominant
mutation of facial development in a transgenic
mouse. The facial malformation was characterized by
a short snout and a twisted upper jaw. The
malformation of the nasal and premaxillary bone was
considered to be secondary to a developmental
defect in the first branchial arch. In the attempt
to establish a mouse model of familial amyloid
polyneuropathy, they microinjected the cloned human
mutant transthyretin gene (176300)
into fertilized eggs. They demonstrated that the
insertion occurred in chromosome 13 of the mouse.
These results were thought to indicate that the
malformation was due to the insertional disruption
of a host gene; however, the possibility that this
mutation was caused by an inappropriate expression
of the injected gene remained to be investigated.
Stein et al. (1995)
tested linkage of 22 candidate genes to CL/P in 11
multigenerational families, and excluded 21 of
these candidates. APOC2 (207750),
which is located at 19q13.1 (or 19q13.2) and which
is linked to the proto-oncogene BCL3 (109560),
gave suggestive evidence for linkage to CL/P. The
study was expanded to include a total of 39
multigenerational CL/P families. Linkage was tested
in all the families, using an anonymous marker,
D19S178, and intragenic markers in BCL3 and APOC2.
Linkage was tested under 2 models, autosomal
dominant with reduced penetrance and affecteds
only. Homogeneity testing on the 2-point data gave
evidence of heterogeneity at APOC2 under the
affecteds-only model. Both models showed evidence
of heterogeneity, with 43% of families linked at
zero recombination to BCL3 when marker data from
BCL3 and APOC2 were included. A maximum multipoint
lod score of 7.00 at BCL3 was found among the 17
families that had posterior probabilities greater
than 50% in favor of linkage. The transmission
disequilibrium test provided additional evidence
for linkage with 3 alleles of BCL3 more often
transmitted to affected children. The results were
interpreted as suggesting that BCL3, or a nearby
gene, plays a role in the etiology of CL/P in some
families.
Wyszynski et al.
(1997) pursued the question raised by the
suggestion that BCL3 on 19q, or a nearby gene, may
play a role in the etiology of nonsyndromic CL/P in
some families. They tested 30 U.S. and 11 Mexican
multiplex families for 4 markers on 19q. While
likelihood-based linkage analysis failed to show
significant evidence of linkage, the transmission
disequilibrium test indicated highly significant
deviation from independent assortment of allele 3
at the BCL3 marker in both data sets and for allele
13 of the D19S178 marker in the Mexican data set.
These results supported an association, possibly
due to linkage disequilibrium, between chromosome
19 markers and a putative CL/P locus.
The division of clefts of the face into those
that include the secondary palate only (the
posterior or soft palate) or cleft palate only, and
those that involve the primary palate and encompass
clefts of the lip with or without the palate is
valid, not only on genetic grounds, but also on
embryologic grounds, since the primary and
secondary palates form independently. Only in the
van der Woude syndrome (119300)
is a mixing of embryologic and genetic types, i.e.,
cleft palate only in some individuals and cleft lip
with or without cleft palate in others, seen with
any frequency (Burdick et
al., 1985). Murray
(1995) reviewed the genetic and exogenous
factors in the causation of facial clefts that have
been demonstrated or suspected. He concluded that
'the strongest evidence implicates a primary gene
on 6p and a role of transforming growth factor
alpha as a modifier of clefting status.'
Mitchell and Christensen
(1996) linked data from 2 centralized data
repositories in Denmark, the Danish Central Person
Registry and the Danish Facial Cleft Database, and
estimated the risks to first, second, and
third-degree relatives of 3,073 CL/P probands born
in Denmark from 1952 to 1987. Analyses of these
data excluded single locus and additive multilocus
inheritance and provided evidence that CL/P is most
likely determined by the effects of multiple
interacting loci. Under a multiplicative model, no
single locus could account for more than a 3-fold
increase in risk to first-degree relatives. These
data provided further evidence that nonparametric
linkage methods, for example, affected relative
pair studies, are likely to represent a more
realistic approach for identifying CL/P
susceptibility loci, than are traditional
pedigree-based methods. However, at least 100 and,
more realistically, several hundred affected sib
pairs are likely to be required to detect linkage
to CL/P susceptibility loci.
Amos et al. (1996)
provided data supporting linkage and association
between chromosome 19 markers in the vicinity of
BCL3 and orofacial cleft. They also presented the
TDT reanalysis of all the affected individuals from
the study of Stein et al.
(1995) because they had detected an error in
the program used for the transmission
disequilibrium test (Amos et
al. (1996)).
The CL/P malformation has been associated with
chromosomal aberrations involving 6p. As noted
previously, Davies et al.
(1995) investigated 3 unrelated cases of CL/P
coincident with 6p region aberrations. They mapped
the breakpoint to 6p24.3 near the HGP22 and AP2
genes, which are potentially involved in face
formation. Linkage studies have yielded both
positive and negative evidence concerning mapping
of CL/P to this region or other regions of the
short arm of chromosome 6. Scapoli
et al. (1997) conducted a linkage study of 38
families using microsatellite markers that mapped
to 6p24-p23. The admixture test, as implemented in
the HOMOG program, was significant when tested
against multipoint data; the lod score calculated,
assuming heterogeneity, was 3.60 at 1 cM telomeric
to D6S259. Taken together, these data were
considered to demonstrate the presence of a locus
for CL/P in the 6p23 chromosome region.
With both case-control- and nuclear-family-based
approaches, Lidral et al.
(1998) screened candidate genes for clefting in
both the CL/P CPO of the nonsyndromic type.
Previously reported linkage disequilibrium for TGFA
could not be confirmed for either CL/P or CPO,
except in CL/P patients with a positive family
history. Also, in contrast to previous studies, no
linkage disequilibrium (LD) was found between BCL3
and either form of clefting. Significant LD was
found, however, between CL/P and both MSX1
(142983)
and TGFB3 (190230)
and between CPO and MSX1, suggesting that these
genes are involved in the pathogenesis of clefting.
In addition, a mutation search in the genes DLX2
(126255),
MSX1, and TGFB3 was performed in 69 CPO patients
and in a subset of CL/P patients. No common
mutations were found in the coding regions of these
genes; however, several rare variants of MSX1 and
TGFB3 were found that may alter their function.
-
SEE ALSO
- Cohen (1978) ;
Eiberg et al. (1987)
; Hecht et al. (1991)
; Lynch and Kimberling
(1981) ; Shields et
al. (1979) ; Van Dyke
et al. (1980)
REFERENCES
- 1. Amos, C.; Gasser,
D.; Hecht, J. T. :
- Nonsyndromic cleft lip with or
without cleft palate: new BCL3 information.
(Letter) Am. J. Hum. Genet.
59: 743-744, 1996.
PubMed ID : 8751880
- 2. Amos, C.; Stein,
J.; Mulliken, J. B.; Stal, S.; Malcolm, S.;
Winter, R.; Blanton, S. H.; Seemanova, E.;
Gasser, D. L.; Hecht, J. T. :
- Nonsyndromic cleft lip with or
without cleft palate: Erratum. (Letter)
Am. J. Hum. Genet. 59: 744 only,
1996.
PubMed ID : 8751881
- 3. Ardinger, H. H.;
Buetow, K. H.; Bell, G. I.; Bardach, J.;
VanDemark, D. R.; Murray, J. C. :
- Association of genetic variation of
the transforming growth factor-alpha gene with
cleft lip and palate. Am. J. Hum.
Genet. 45: 348-353, 1989.
PubMed ID : 2570526
- 4. Beiraghi, S.;
Foroud, T.; Diouhy, S.; Bixler, D.; Conneally,
P. M.; Delozier-Blanchet, D.; Hodes, M. E.
:
- Possible localization of a major
gene for cleft lip and palate to 4q.
Clin. Genet. 46: 255-256, 1994.
PubMed ID : 7820940
- 5. Bixler, D.;
Fogh-Andersen, P.; Conneally, P. M. :
- Incidences of cleft lip and palate
in offspring of cleft parents.
Clin. Genet. 6: 83-97, 1971.
- 6. Burdick, A. B.;
Bixler, D.; Puckett, C. L. :
- Genetic analysis in families with
van der Woude syndrome. J.
Craniofac. Genet. Dev. Biol. 5: 181-208,
1985.
PubMed ID : 4019732
- 7. Carter, C. O.;
Evans, K.; Coffey, R.; Roberts, J. A. F.; Buck,
A.; Roberts, M. F. :
- A three generation family study of
cleft lip with or without cleft palate.
J. Med. Genet. 19: 246-261, 1982.
PubMed ID : 7120312
- 8. Chenevix-Trench,
G.; Jones, K.; Green, A.; Martin, N. :
- Further evidence for an association
between genetic variation in transforming growth
factor alpha and cleft lip and palate.
(Letter) Am. J. Hum. Genet.
48: 1012-1013, 1991.
PubMed ID : 1673285
- 9. Chenevix-Trench,
G.; Jones, K.; Green, A. C.; Duffy, D. L.;
Martin, N. G. :
- Cleft lip with or without cleft
palate: associations with transforming growth
factor alpha and retinoic acid receptor
loci. Am. J. Hum. Genet. 51:
1377-1385, 1992.
PubMed ID : 1361101
- 10. Chung, C. S.;
Bixler, D.; Watanabe, T.; Koguchi, H.;
Fogh-Andersen, P. :
- Segregation analysis of cleft lip
with or without cleft palate: a comparison of
Danish and Japanese data. Am. J.
Hum. Genet. 39: 603-611, 1986.
PubMed ID : 3788974
- 11. Cohen, M. M.,
Jr. :
- Syndromes with cleft lip and cleft
palate. Cleft Palate J. 15:
306-328, 1978.
PubMed ID : 281275
- 12. Crawford, F.
C.; Sofaer, J. A. :
- Cleft lip with or without cleft
palate: identification of sporadic cases with a
high level of genetic predisposition.
J. Med. Genet. 24: 163-169, 1987.
PubMed ID : 3572999
- 13. Curtis, E. J.;
Fraser, F. C.; Warburton, D. :
- Congenital cleft lip and
palate. Am. J. Dis. Child.
102: 853-857, 1961.
- 14. Davies, A. F.;
Stephens, R. J.; Olavesen, M. G.; Heather, L.;
Dixon, M. J.; Magee, A.; Flinter, F.; Ragoussis,
J. :
- Evidence of a locus for orofacial
clefting on human chromosome 6p24 and STS
content map of the region.
|
