Download The genetics of mental retardation

The genetics of mental retardation
Jonathan Flint and Andrew O M Wilkie
Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK
We review the advances that have been achieved using molecular genetic
techniques to characterise the genetic basis of mental retardation in recognised
syndromes and in discovering new genetic conditions that give rise to mental
retardation. However, even with the cloning of a number of mutant genes, the
pathogenesis of the condition is not understood. The genetics of mental retardation
are turning out to be remarkably complex and are likely to remain a challenge for
clinicians and scientists for years to come.
Interest in the genetics of mental retardation (MR) has grown with the
realisation that the application of molecular techniques can make
substantial inroads on the old problems of aetiology and pathogenesis.
There is now the real possibility of describing how a discrete biological
insult gives rise to the complex cognitive and behavioural features that
characterise MR. There are three major areas of development. First, there
has been progress in delineating the genetic determinants of MR, which
promises to reduce the number of cases classed as idiopathic. Second, the
molecular basis of a number of syndromes associated with MR has been
described, thus beginning to explore the pathogenesis of the condition.
Finally, researchers are now attempting the molecular analysis of forms
of MR that have a polygenic component.
Advances in determining the genetic origin of MR
It is still true to say that the cause of MR is unknown in the majority of
cases. A diagnosis (genetic or environmental) is reached in about 64% of
the group with IQ less than 50, but this figure drops to approximately
24% in the IQ 50-70 group1"6. Among known causes, the two largest
individual contributors to MR are genetic in origin (Down syndrome and
the fragile X syndrome). Over 500 other genetic diseases, mostly very
rare, have also been associated with MR7-8 and it is reasonable to suppose
Con-eipondence to: that a considerable proportion of cases of unknown aetiology have a
DrJonathan Hint, inMute genetic origin. Can we estimate what that proportion is?
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©Tti. British Council 1996
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good indication of what can be achieved with current diagnostic
practices. About half (60 of 115) 'undiagnosed' patients were thought
to have a genetic cause, 20 based on recognition of a dysmorphic
phenotype and 40 on family history. In the group with mild MR (IQ 5070), psychosocial disadvantage and polygenic inheritance of susceptibility loci have long been considered the major contributors. In support
of this view, children adopted by parents of high socio-economic status
have higher IQ scores than children adopted by parents of low socioeconomic status10 and there is a relatively high recurrence risk among
relatives of those with mild idiopathic MR6-11. However, it should also be
noted that there is an excess of chromosomal abnormalities12 and
physical handicaps13. In summary, genetic defects may account for over
half of idiopathic MR where the IQ is less than 50. Available data do not
allow us to estimate a similar figure for the IQ 50-70 group, but there are
indications that single gene conditions and chromosomal abnormalities
may be more frequent than previously assumed.
The fact that so many different genetic disorders give rise to MR
suggests that idiopathic MR will also be aetiologically heterogeneous.
Recent work has tended to confirm this view as new syndromes and new
genetic mechanisms are discovered, and the genetic basis of existing
disorders described. These are discussed in the following sections where
we have categorised the disorders into inherited and sporadic forms.
Inherited forms of MR
Progress in delineating the genetic basis of inherited forms of MR is at
present largely restricted to cases of X-linked MR (XLMR), because only
X-linked recessive disease is compatible with the occurrence of affected
members in multiple generations. XLMR is important because it is
common: overall the frequency of XLMR is estimated to be 1.8 in 1,000
males with a carrier frequency of 2.4 in 1,000 females14. Currently, 127
XLMR conditions are known15 and the availability of dense genetic maps
means that few families are required to confirm the suspicion of X-linked
inheritance: 53 loci have been mapped to date.
Mapping inherited forms of XLMR has provided an unsuspected clue
about the genetic aetiology of MR. The distribution of XLMR is not
random across the X chromosome, suggesting that some conditions may
be allelic variants of each other, or that there is a clustering of genes
involved in brain function16. Thus, following the mapping of X-linked
hydrocephalus to Xq28 and the subsequent identification of a defective
candidate gene17, it was possible to ask whether other syndromes in the
same region might be allelic variants. It turns out that X-linked spastic
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The genetics of mental retardation
paraplegia syndrome, MASA syndrome and X-linked hydrocephalus
result from different mutations in the same gene (a neural cell adhesion
molecule, Ll)18>19. Similarly, once the dysmyelinating disorder, PelizaeusMerzbacher disease, was found to be due to mutations in the proteolipid
protein gene on Xq21 20 , it was discovered that mutations in the same
gene gave rise to another form of X-linked spastic paraplegia21
Mapping and cloning of the commonest form of XLMR, fragile X
syndrome, has led to the recognition of a new form of inherited MR.
Individuals with fragile X syndrome have a folate-sensitive fragile site in
Xq27.3 associated with an expansion of a trinucleotide repeat (CGG),
discussed in more detail below. Following the molecular characterisation
of the fragile site, known as FRAXA, it became clear that there were
some families with XLMR who were fragile site positive but did not have
a CGG expansion at FRAXA. Two more fragile sites, termed FRAXE
and FRAXF were identified22"24, both of which are now known also to be
associated with expansions of CGG repeats25"27. In contrast to the
situation with FRAXA where there has been considerable work
characterising the phenotype, FRAXE and FRAXF have been denned
more fully at a genetic than at the phenotypic level. FRAXF is almost
certainly not associated with MR, as the repeat expansion segregates
independently of mental impairment. CGG expansion at FRAXE is much
more likely to be a cause of mild MR, though affected males and females
do not otherwise show a specific clinical phenotype 28 .
Sporadic forms of MR
Despite these achievements, the percentage of syndromes mapped or
characterised at a molecular level is still small, and we have yet to see
molecular mapping and cloning approaches substantially reducing the
number of cases of idiopathic MR. The characterisation of sporadic cases
of MR with a genetic origin might seem a harder task than linkage
analysis. However there has been success in the identification of new
cases of chromosomal rearrangements, in some instances leading to the
identification of more subtle mutations in genes. This has been achieved
in three ways.
First, molecular analysis has revealed the presence of chromosomal
rearrangements in syndromes that previously had no known cause. Two
recent examples are Williams and Rubinstein-Taybi syndromes. Williams
syndrome is diagnosed on the basis of developmental delay, characteristic
face and a heart defect (supravalvular aortic stenosis (SVAS), peripheral
pulmonary artery stenosis)29. Identification of the molecular pathology
came about through genetic mapping to chromosome 7 q l l of a locus
that predisposed to SVAS30 and the investigation of a unique family in
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which a translocation disrupted the elastin gene, a candidate locus for
SVAS31. Since SVAS occurred in Williams syndrome, researchers
hypothesised that there might be deletions affecting both the elastin
locus and nearby genes with other functions which, when monosomic,
would contribute to other features of the Williams phenotype. About
90% of cases of Williams syndrome have turned out to have deletions at
the elastin locus32.
In the case of Rubinstein-Taybi syndrome (RTS), a sub-microscopic
deletion was found because a few RTS patients had translocations
involving chromosome 16pl3.3. RTS is another rare sporadically
occurring cause of MR, diagnosed on the basis of a characteristic facial
appearance and broad thumbs and big toes. Six of 24 cases assessed using
fluorescence in situ hybridisation had sub-microscopic deletions of
16pl3.3 33 . Subsequent work has identified the gene for CREB binding
protein (CBP) as a candidate for the syndrome34. CBP is involved in a
cellular signalling pathway (cAMP regulated gene expression) which may
explain the combination of multiple congenital anomalies and mental
retardation as part of a generalized dysregulation of gene expression.
Second, in the case of DiGeorge syndrome the clinical variability
associated with rearrangements in the same chromosomal region together
with the features held in common with other syndromes has revealed that
deletions in the same region of chromosome 22q are responsible for a
number of other syndromes. DiGeorge syndrome is characterised by
absence or hypoplasia of the thymus and parathyroid glands, cardiac
malformations, dysmorphic facial features and a variable degree of
developmental delay35. Many (but not all) cases have a deletion of the
proximal long arm of chromosome 22 (22qll). It has been shown that
22qll deletions can be associated with a variety of isolated congenital
heart defects and also with the velo-cardio-facial (VCF) syndrome (of
which developmental delay is a characteristic feature)36.
Consideration of phenotypic variability also led to the molecular
detection of a new syndrome due to a sub-microscopic chromosomal
duplication. At least 1 in 1,000 males is missing about half of the long
arm of the Y chromosome37. Most frequently the associated phenotype is
short stature and azoospermia, but severe retardation and dysmorphic
features have also been reported. The reason for this variability turns out
to be due to misaligned exchanges between Yq and Xq, resulting in the
presence of Xq DNA on a truncated Yq chromosome38. Affected males
have microcephaly, hypotonia and severe MR and the syndrome has
been called XYXq in reference to the fact that the responsible lesion is
failure of the normal X-inactivation mechanism of dosage compensation
of a gene, or more likely genes, on the tip of the long arm of the X
chromosome. The question that now needs answering is how many cases
of idiopathic MR in males are due to submicroscopic disomy of Xq.
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Third, rearrangements involving the terminal or subtelomeric regions
of chromosomes have been suggested to contribute to about 6% of
idiopathic MR39. Routine cytogenetic analysis indicates that chromosomal anomalies occur in 40% of severe and 10-20% of mild MR. Since
small rearrangements (of the order of 1-2 megabases (Mb) of DNA) are
undetectable even at the highest resolution of chromosome analysis, it is
likely that such sub-microscopic chromosomal rearrangements are
present in a proportion of individuals with idiopathic MR. Cytogenetically invisible rearrangements of chromosome ends (telomeres) have been
shown to be the cause of MR in a number of conditions40^2 so a search
for subtelomeric abnormalities appeared worthwhile. Molecular methods
of detection are feasible: rearrangements can be inferred from the
abnormal inheritance of alleles at a locus. In a survey of 99 cases of
idiopathic MR, three cases of monosomy were found, two of which were
unbalanced translocations39. Given the low sensitivity of the test used, the
true prevalence of subtelomeric rearrangements in idiopathic MR was
estimated to be 6%.
Molecular pathogenesis of mental retardation
The molecular characterisation of MR syndromes is the first step towards
understanding how a genetic lesion gives rise to MR. We can categorise
these genetic lesions into two types: first, mutations that inactivate or
alter the function of a single gene; second, abnormal gene dosage due to
increased copy number (as in trisomy) or haploinsufficiency (as in
deletions that leave the individual with only a single copy of a gene). In
terms of understanding the pathway from genotype to phenotype, these
two categories are often thought to overlap because of evidence
suggesting that in syndromes with chromosomal rearrangements there
are critical regions where the rearrangement has its effect by inactivating
a single gene. Here we discuss the two groups separately.
Single gene conditions
It has long been appreciated that mutations in single genes can result in
MR, the egregious examples being inborn errors of metabolism.
However it is also generally true that this knowledge has not
substantially advanced our understanding of the pathogenesis of MR.
Nor can it be said that the advent of molecular cloning strategies has cast
much new light on this problem. Molecular techniques have given us very
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detailed information about what has gone wrong with a gene, but not yet
taught us much about the consequence of that lesion.
The mutations that have been found in genes responsible for MR
generally result in a loss of function in that gene expression is either
reduced or abolished. In the case of the fragile X syndrome the process is
thought to account for some of the variability in the clinical phenotype
and deserves particular consideration. Inactivation of the FMR 1 gene is
the cause of fragile X syndrome, as we know from the description of
patients with a fragile X like phenotype who have deletions and point
mutations in the gene43"45. However the commonest cause of FMR1
inactivation is the amplification of the CGG trinucleotide repeat situated
upstream of the coding region of the gene46. The repeat varies from 5 to
53 repeats in normal individuals; it is over 200 units long in affected
individuals. Repeats longer than 200 directly impede translation of the
FMR1 gene47.
Genetic variation in the fragile X syndrome can be correlated with the
phenotype in a number of ways. First, variation in the size of the CGG
repeat array relates to the phenotype. Fragile X syndrome does not
exhibit a classical Mendelian pattern of X-linked inheritance: males can
be carriers (normal transmitting males). Carrier males and some carrier
females have repeat expansions from 43-200 trinucleotides and are
asymptomatic. Expansions of this size are called pre-mutations. Second,
another structural alteration that affects FMR gene expression has been
described: methylation of the FMR1 gene, almost always found in
affected individuals. Third, a large fraction of fragile X males with the
full mutation have a premutation in a percentage of cells (i.e. they are
somatic mosaics), though it is not known how this finding in blood cells
reflects the degree of mosaicism in the CNS. A number of investigators
have attempted to correlate the phenotypic variability found in fragile X
with these genetic variables, but it is still too early to say how far the
genetic variation can account for the phenotype48"51.
While observations of the structure of mutations might give some clues
about the origins of variability of the clinical phenotype, we can expect to
learn much more about the pathogenesis of MR from a knowledge of
gene function. Research here is still at a very early stage. Perhaps the only
finding is that no general mechanism is suggested, which is not surprising
given the heterogeneity of MR and the genetic and biological complexity
of brain development and function.
The extent of our ignorance is well revealed by the state of knowledge
of two recently cloned genes. The FMR1 gene almost certainly acts by
regulating expression of other genes. It produces a protein that binds
RNA in vitro and may well do so in vivo52-53. What it does other than
that is still unknown, but one way to find out is to use genetic techniques
to make an animal model of the disorder. This has now been achieved by
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inactivating the mouse homologue of FMR154. The animal has physical
features in common with fragile X patients and it is claimed to have
similar psychological difficulties. Clearly the extrapolation of psychological tests used on the mouse to human behaviour requires caution, but
we can expect further work to explore the normal role of FMR1.
The cloning of a gene for the ATR-X syndrome has also revealed a
gene that acts by regulating other genes. ATR-X is a rare disorder that
was first noticed because of an association between a blood disorder (athalassaemia) and MR55. Molecular techniques were used to define a new
XLMR syndrome56 and to clone the responsible gene, termed XH257.
Since ATR-X patients have a haematological disorder, urogenital
abnormalities and MR, XH2 almost certainly acts on numerous
pathways, probably by altering chromatin structure57.
In two other XLMR conditions, genes have been identified whose
normal function is known, but unfortunately this has still not taught us
much about MR pathogenesis. LI CAM is a neural cell adhesion molecule
involved in neuronal migration and differentiation. Mutations result in
X-linked hydrocephalus, spastic paraplegia and MASA syndrome18-19.
The spasticity observed in all three syndromes, the absence of the
corticospinal tract in severe cases of X-linked hydrocephalus and the
observation that LI is expressed at high level during the development of
this tract in the rat combine to suggest that mutations in LI have their
effect through disrupting the development of specific neuronal tracts58,
though how this results in MR is unknown. In the second example, a role
for disordered monoamine metabolism in the aetiology of mild MR
emerges from the work of Brunner and colleagues, who reported a family
where all affected males showed mild MR and impulsive aggression.
They localised a gene to Xpll-p21 and went on to show that affected
individuals had disturbed monoamine metabolism due to a point
mutation in the gene for monoamine oxidase A (MAOA)59-60.
Chromosomal abnormalities
Chromosomal abnormalities are thought to have their effect by altering
gene dosage. In the simplest scenario, autosomal deletions halve gene
expression in the monosomic region, while in trisomic regions there is
overexpression by 50% or more. In general agreement with this view, the
larger the chromosomal abnormality, the more severe the phenotype, but
sometimes the picture is more complicated.
First, it is now clear that simply having two copies of a chromosomal
region does not guarantee normal IQ. At some loci, correct gene dosage
requires that one locus is inherited from the father and one from the
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mother. Genes regulated in this way are said to bear a parental imprint.
The best example in human genetics of this phenomenon is the difference
between the Prader-Willi (PWS) and Angelman syndromes (AS)61. Both
can arise from deletions of the same chromosomal region: 15qll-ql3. If
the deletion occurs on the paternally inherited chromosome the
phenotype is PWS; if the deletion is on the maternal chromosome the
phenotype is AS. About a third of PWS patients have two intact
chromosome 15s, but have inherited both from their mother and are thus
said to have maternal uniparental disomy. Conversely some non-deletion
cases of AS arise from paternal uniparental disomy. Molecular
characterisation of the deletions on 15qll has indicated that there are
two critical regions, one for PWS and one for AS62"64 Nevertheless, it is
believed that both syndromes arise from mutations that disrupt the
imprinting process61'65.
Second, chromosomal deletion syndromes are notorious for the
variability of their associated phenotypes. Part of the explanation lies
in the differing sizes of the responsible deletions, but this does not explain
the phenotypic variability seen within a single family. A number of
hypotheses have been advanced: monosomic regions may contain
recessive mutations that are unmasked by the loss of the second copy66;
background genetic effects will alter the phenotype67; non-genetic factors
may play a role. However the relative contribution of these mechanisms
is not known.
Despite the difficulties of assessing the genotype/phenotype relationship in MR syndromes that arise from chromosomal abnormalities, there
is general agreement that the number of genes responsible for a syndrome
may be relatively small. Candidate genes for a number of haploinsufficiency syndromes have now been isolated and while many of these may
not be responsible for the MR that is part of the syndrome it is likely that
in the next few years some candidates will be discovered68.
Polygenic mental retardation
The extent to which IQ is genetically determined has been a subject of
intense debate, but the fact that genes play some part has not been
seriously disputed. Chromosomal mapping of loci that determine genetic
variability in multifactorial conditions is now possible69 and the
technique may be appropriate for localising the genetic basis of MR.
Indeed attempts have already begun to map the loci determining
quantitative variation (QTL) in IQ70.
QTL mapping will not work on genetically heterogeneous conditions,
of which severe MR is a very good example. Many cases of mild MR may
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British Medical Bull«tin}99622 [No. 3)
The genetics of mental retardation
be due to variation in the same set of genes, but lack of good twin and
family studies of mild mental impairment means we cannot be sure of
this. Assuming that the approach does work and that localisations are
found, we are faced with the question whether genes that determine
variation in IQ overlap with the genes already implicated in MR. So far,
work has concentrated on molecular pathology, that is mutations that
disrupt gene function. QTL mapping might localise DNA variants that do
not inactivate genes but alter their function in a much less dramatic way.
Conceivably the same pathways could allow both types of variation, in
which case the combination of QTL mapping and molecular pathology
screening would be ideally placed to identify the many genes that are
responsible for MR.
Key points for clinical practice
The genetics of MR is proving to be one of the most complex fields of
human genetics; the combination of aetiological heterogeneity, the small
numbers of individuals with the same disorder and the unexpected
complexity of the genetic basis of MR (for example fragile X, PWS and
AS) have slowed progress. One of the lessons that emerges is the need for
obsessional clinical and molecular genetic investigation of individual
families. The discovery of new syndromes and the characterisation of
critical chromosomal regions for particular disorders have only come
about because of attention to rare cases which appeared to be exceptions
to general rules: patients with the phenotype of PWS but no obvious
deletion provided evidence for genomic imprinting; rare families where
sporadic disorders were present in more than one family member have
provided important gene localising information.
The phenotypic heterogeneity of MR deserves more clinical interest
than it currently receives for another reason. 'Pure' MR is very rare; it is
frequently accompanied by other behavioural abnormalities and
psychiatric disorders. In many instances this has been correctly attributed
to environmental influences but in some syndromes specific behavioural
patterns appear genetically determined (the best example being selfmutilation in Lesch-Nyhan syndrome)71. These behavioural phenotypes
may provide a way of characterising the genetic basis of behaviour as was
demonstrated in the family where mild MR and impulsive aggression
were attributed to a mutation in the MAOA gene. Had it not been for the
initial clinical observation that a behavioural abnormality showed a
pattern of X-linked inheritance, the molecular genetic discovery would
not have been possible. We can expect further advances in this field
attributable to clinical skills.
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