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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? of Molecular Medicine, A • • • i i i T-> in o r -•> ^<i John Raddith, Hospital, ^ institution-based survey by Fryns and colleagues9 of 262 OxfordOX3 9DU, UK moderately retarded adults (defined in their study as IQ 30-55) gives a Britith Mmdkal Bulletin 1996;52 (No. 3):453-464 ©Tti. British Council 1996 Biological psychiatry 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 454 Britith Medical Bulhtin 1996^2 (No. 3) 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 British Medical Bulletin 1996;52 (No. 3) 455 Biological psychiatry 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. 456 British M.dical Bu/Un 1996^2 (No. 3) The genetics of mental retardation 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 BriH.fi M»<£cal Bulletin 1996^2 (No. 3) 457 Biological psychiatry 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 458 Brih'ih Mmdical Bulletin 1996^2 (No. 3) The genetics of mental retardation 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 Brihsh M*dkal Bulletin 1996;52 (No. 3) 459 Biological psychiatry 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 460 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. Snhsh Medical Bufbtin 1996;52 (No. 3) 461 Biological psychiatry References 1 Hagberg B, Hagberg G, Lewerth A, Lindberg U. Mild mental retardation in Swedish school children. I. Prevalence. Acta Paedutr Scand 1981; 70: 441-4 2 Hagberg B, Hagberg G, Lewerth A, Lindberg U. Mild mental retardation in Swedish school children. II. Etiologic and pathogenetic aspects. Acta Paediatr Scand 1981; 70: 445-52 3 Lamont MA, Dennis NR. Aetiology of mild mental retardation. 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