Download Genes and Cleft Lip and Palate

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Genes and cleft lip and palate
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In order to study the causes of clefting, clefts are categorised into two groups. Those that are
associated with changes of the function or formation of other parts of the body are called syndromic
clefts. The other group, comprising the large majority, are not associated with changes elsewhere in the
body and are called nonsyndromic clefts or isolated clefts.
The word “syndrome” comes from the Greek words for “running together”. Syndromes are patterns
of features that are seen together in different people, suggesting that they might have the same
underlying cause. An example of a syndrome is the association of dimples or depressions in the lower
lip with cleft lip, plus or minus cleft palate. These features are seen together in van der Woude
syndrome, which is due to a single gene passed from affected parent to affected child. Many syndromes
are entirely due to inheritance of a single gene, as is van der Woude syndrome, others are not inherited
but are due to disturbance of the fetal environment, such as fetal alcohol syndrome. Some syndromes
that are known to be inherited could recur in a future child in the family. Syndromes that are due to
environmental effects will not recur if the environmental factors can be recognized and avoided in
future. So it is important for a syndrome to be recognised, because accurate diagnosis enables accurate
genetic counselling.
Genetic counselling is defined as a process where people at risk of a disorder that may be inherited are
advised of the risks and consequences of having the disorder, the chance that they might develop or
transmit the disorder, tests that can be performed to refine these chances, and options for treatment or
cure (Harper, PS, 1984. Practical Genetic Counselling. Oxford University Press, London). If people
with clefts or their families want to have genetic counselling, this should include a diagnostic assessment
for the presence of a syndrome in association with the cleft. A diagnostic assessment might just consist
of a history and physical examination, in which are assessed the person’s growth and developmental
progress, external formation of the body including the nose, ears and eyes and mouth, the presence of
heart murmurs, etc. Sometimes an ultrasound examination of the heart (echocardiogram), hearing or
vision test, X rays, chromosome test or a DNA test for a specific gene are organised if a syndrome is
suspected or identified. For some syndromes there are no diagnostic tests available yet, and the
diagnosis rests solely on clinical criteria. These are be the results of history, physical examination and
judgement of the geneticist based on clinical experience with other cases. Clinical photographs of the
external features of the syndrome can be presented with other clinical details to experienced colleagues
to make sure that other experts contribute to the diagnosis. Computer databases can now be used to
check diagnoses by comparing clinical details and photographs with those of other people known to
have the syndrome. Genetic testing is available for some syndromes to confirm the diagnosis and detect
the presence of the gene in carriers. If no syndrome is detected on physical examination, no further
tests are usually required. Often a paediatrician is the first person to detect features suggestive of a
syndrome, and this often leads to referral to a genetics service to determine or confirm if a syndrome is
present.
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Non-syndromic clefts
If no syndromic features are present, and the cleft is determined to be nonsyndromic, then the cause is
usually deemed to be multifactorial. This means that the cleft was caused by a combination of effects of
genes inherited from both parents, and factors present in the environment of the fetus before and during
the time of palate development (5-9 weeks after conception). Only a small minority of genes and
environmental effects are known. In contrast to single-gene conditions that are often associated with
syndromic clefts, the effects of individual genes that contribute to multifactorial disorders are too weak
to cause a cleft by themselves. They can only increase susceptibility to clefting and a cleft only occurs if
a sufficient number of genes are inherited, in association with appropriate environmental exposures for a
threshold to be crossed so that the developing parts of the lip or palate do not meet completely during
embryonic development. Because it is usually not possible to identify genes or environmental effects,
future children cannot be tested for the presence of a cleft unless it is identified on a prenatal ultrasound
scan. In the past few years, research into genes for growth factors or their cellular receptors has shown
that some, such as the gene for transforming growth factor beta (TGFβ) influence susceptibility to
clefts. The information arising from these experiments is still not definitive enough to contribute to
genetic counselling.
Empiric (observed) figures have been determined for the chance that a relative might be born with a
cleft. The following are taken from a published table (Harper, 1984). Chances that a person will be
born with a cleft are indicated as percentages (the probability of the event in chances out of one
hundred).
Affected relative:
Sibling: no family details available
Sibling: family history known to be
negative
2 affected siblings (i.e. brothers or
sisters)
1 sibling + 1 parent
1 parent
2nd degree relative (i.e. grandparent,
uncle, aunt)
3rd degree relative (i.e. cousin)
General population incidence
Cleft lip ± cleft
palate
4%
2.2%
Cleft palate
only
1.8%
10%
8%
10%
4.3%
0.6%
3%
0.3%
0.1% (1/1000)
0.04%
(1/2500)
Recurrence figures are different for cleft palate as distinct from cleft lip/palate. Families exist where
affected relatives just have cleft lip, and in other families the affected relatives all have isolated cleft
palate. This indicates that the embryological processes of fusion of the lip and palate might share some
genes, but they do not share other genes. It can be seen from the table that only a minority of relatives
would be expected to have a cleft when the affected relative has a nonsyndromic cleft. This is because
the person who had the cleft inherited a number of susceptibility genes for clefting, probably from both
parents, and there is only a low likelihood that a relative, even a sibling, will inherit the same number of
genes from both parents or be exposed to the same environmental conditions.
The following table (once again, the percentage chance that a person will have a cleft if their sibling is
affected) shows that chances for a person to have a cleft lip or palate increase in proportion to the
extent of the sibling’s cleft. This suggests that more markedly affected people have inherited a bigger
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“dose” of genes for clefting (either a greater number of predisposing genes, or predisposing genes of
greater severity), so their siblings have a greater genetic predisposition.
Extent of cleft in affected sibling
Bilateral (both sides) cleft lip with cleft
palate
Unilateral (one side) cleft lip and palate
Unilateral cleft lip
Percentage chance of having a
cleft
5.7%
4.2%
2.5%
Environmental factors that are known to influence susceptibility to clefts include maternal hyperthermia
(excess temperature inside the uterus during some stage of lip or palate development), maternal
smoking or alcohol intake, maternal phenylketonuria, administration of large doses of cortisone-like
medications to the mother and administration of hydantoin (Dilantin) for maternal epilepsy. These are
known to play some part in the causation of clefts because the proportion of babies with clefts who are
exposed to each of these agents is significantly, but often only slightly, higher than the exposed
proportion of babies without clefts. Many women who are exposed to these medications have to
continue them knowing that the underlying problem might be more dangerous to the baby than the
treatment.
Syndromic clefts
The individual features of a syndrome, such as eyes that are set further apart than usual, or height less
than average, might be seen very frequently as isolated features in the general population. By
themselves these mean nothing, it is just when a combination of features are present within the same
person or group of people that a syndrome is suspected. When a syndrome is diagnosed it can often be
distressing for the person or their family to discover a wide variety of things that can go wrong in
association with the syndrome. It is important to realise that no person with a syndrome has every
feature: the list of features seen might be compiled from the summed experience of many people with
the syndrome. Some people within a family who have inherited the same genes for a syndrome might
have entirely different manifestations. For example a girl with velocardiofacial syndrome (VCFS: velo
means palate, this syndrome can be associated with complete or submucous clefts of the palate) might
have severe congenital heart disease such as an interrupted aortic arch, and no cleft at all, whereas her
mother who has a normal heart might have required pharyngoplasty because her palate did not function
properly. They both have the same syndrome and it is caused by exactly the same genes, although other
genes an environmental influences the two relatives do not share might have modified the effects of the
VCFS in each case. It is also important to remember that early in the description of syndromes, only
people with the most marked manifestations are diagnosed. Later, as geneticists become better
acquainted with the syndrome, people with milder manifestations are discovered to have the same
condition, so not every person who has a syndrome needs to have any of the more severe
complications.
Once the diagnosis of a syndrome is made, it is possible to tell the person and their family about the
range of severity, from the experience of people diagnosed previously, reported in the medical literature
or increasingly in the internet home pages or newsletters of support groups (like Cleft Pals). The form
of inheritance can be used to determine the chance that anyone else in the family will develop or
transmit the syndrome. There are three major types of inheritance for single-gene (or Mendelian)
conditions, in which the effect of a single altered gene is sufficient to cause a cleft, without the need for
a contribution from other genes or environmental influences:
•
Autosomal dominant inheritance. Mendel’s experiments showed that most genes of creatures
that reproduce sexually are present in pairs, one member of each pair having come from one
parent, and the other member of each pair having been inherited from the other parent. Our
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genes are like strings of beads, each bead in the string representing one of four chemicals
called DNA nucleotides. The sequence of these nucleotides is a code that is read by the cells
of our body, and acts as a recipe for a substance made in our body. There are probably
100,000 pairs of genes in each cell of our body. It follows that the cells of our body ar
potentially able to make 100,000 different substances in order to grow and develop from the
single cell present at conception, into a healthy adult consisting of billions of cells. Each cell
has a copy of the original set of genes present at conception, because each time a cell divides
into two, the two new cells receive identical copies of the entire set of genes. If a mutation
(alteration of the sequence of nucleotides) is inherited in the egg or sperm, it will therefore be
present in every body cell. The genes, along with intervening stretches of non-coding DNA,
are joined together end to end to form 23 pairs of long tangles of DNA called chromosomes.
Although genes are usually too small to see with a microscope, it has been possible to use this
tool to count and examine chromosomes accurately since the late 1950s. When sperm or egg
cells are made, they receive one chromosome from each pair, so that at fertilisation the new
embryo has a complete set of 23 pairs, containing genes inherited from both parents. It is
just a matter of chance, like flipping a coin, which chromosome in each pair is put into a
particular sperm or egg cell. The chromosomes are numbered in order of decreasing size
from 1-22. Pairs number 1-22 look the same in males and females and are called autosomes,
whereas the 23rd pair are called the sex chromosomes: females have two middle-sized X
chromosomes while males have a single X and a much smaller Y chromosome. In autosomal
dominant forms of clefting, only one gene in the pair needs to be altered for the carrier to
have a cleft. The gene is present on one of the autosomes, i.e. chromosomes number 1-22.
Even though the other gene in the pair has the usual DNA sequence it cannot compensate for
the altered gene. When a person with this type of gene has children, there is one chance in
two that the child will inherit the altered gene and have a cleft. On the other hand there is an
equal one chance in two that the child will inherit the other normal gene and will not have a
cleft or pass the condition on. It can be seen that it is important to diagnose Mendelian forms
of syndromic clefting because the recurrence risk is 50% if a parent carries the gene, much
higher than the recurrence figures for non-syndromic clefting. The most common forms of
syndromic clefting seen in the cleft palate clinic, velocardiofacial syndrome, Stickler
syndrome and some forms of Opitz syndrome are autosomal dominant, and family histories
of these conditions might show affected people in several generations. Male to male
transmission is a feature of autosomal dominant inheritance, i.e. sons can inherit the gene
from their affected fathers, which is not possible in X linked inheritance. Variable expression
is another feature, in which different relatives who have the same gene have a different
severity or spectrum of effects even though they have the same gene. Variable expression
may be explained by differences in other genes or different environmental influences. New
mutations occur with variable frequency. A new mutation has appeared for the first time in
the egg or sperm that formed the affected person, so there is a significant risk only for that
person’s children. Occasionally what appears to be a new mutation in an affected child is
actually present in a proportion of one parent’s body cells (called somatic mosaicism if it
involves the parents body cells, or germ-line mosaicism if the cells that form eggs or sperm
are involved). There is a chance of another affected sibling if there is germ line mosaicism in
a parent..
•
Autosomal recessive inheritance. This differs from autosomal dominant inheritance in that both
genes in a pair need to be altered for a child to be affected. Affected people inherit one altered gene
from each parent. The carrier parents are not affected because they have only one copy of the
altered gene, and the other normal gene in the pair can compensate for the altered one. If a child
has an autosomal recessive condition each sibling has one chance in four of being affected, one
chance in four of inheriting the two normal genes and two chances in four of being a carrier.
Children who are carriers have a low chance of marrying a carrier unless their partner also has a
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family history of the same condition, as most recessive genes are rare. Recessive forms of clefting
are rare, and include diastrophic dysplasia and Roberts syndrome.
•
X-linked inheritance. Genes on the X chromosome affect males more severely because they only
have a single X chromosome, whereas females have a normal gene on their other X chromosome
that compensates fully or partially. There are four equally likely possibilities for children of women
who carry an X linked gene. One is an affected son who has inherited the X chromosome with the
altered gene, one is a carrier daughter, one is a non-carrier daughter and the last is a boy who has
inherited the normal X. Boys who carry X linked conditions pass the gene on to all their daughters
who must inherit their father’s only X chromosome, but none of their sons will be affected because
they inherit their father’s Y chromosome. Examples of X linked clefting conditions include the X
linked form of Opitz syndrome and some forms of orofaciodigital syndrome.
•
Chromosomal conditions. Children with a disturbance in the number of chromosomes, such as an
extra complete chromosome (trisomy, like Down syndrome) an extra piece of chromosome joined
to one of the others (translocation or insertion) or a missing piece of chromosome (chromosome
deletion) usually have a syndrome. This is because so many genes are likely to be altered in number
if the disturbance in chromosome constitution is large enough to be diagnosed by microscope study
in the cytogenetics laboratory.
Sporadic syndromes associated with cleft palate
A number of syndromes have no known cause yet, and show little evidence of being inherited, because
Examples include Kabuki syndrome, facioauriculovertebral (Goldenhar) spectrum and de Lange
syndrome. Many are likely to be new autosomal dominant mutations, and some could be contiguous
gene deletion syndromes, where several neighbouring genes are deleted or lost from a chromosome in
the making of an egg or sperm cell. In velocardiofacial syndrome a contiguous gene deletion of a
number of genes on the long arm of chromosome 22 can be inherited by several members of a family,
and diagnosed by a special chromosome test call fluorescent in situ hybridisation (FISH). The number
of conditions that can be tested this way is likely to increase as chromosomal locations are discovered
for each syndrome.
Matt Edwards
Hunter Genetics
September 1998
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