BRITISH JOURNAL OF PSYCHIATRY (2000), 176, 12^19

Genetics advances and learning disability{{ conditions are genetically heterogeneous (e.g. tuberous sclerosis). On a larger scale, manymanygenesgenes can be affected by structural WALTER J. MUIR abnormalities of chromosomes. Duplica- tions, with associated effects on gene dosage, can range from small partial triso- mies through to the complete . Karyotyping now involves molecular cytogenetics, with high resolution banding and fluorescent in situinsitu hybridisation (FISH) revealing new sub-microscopic chromoso- mal rearrangements well below the classical Background Medicine is rapidly Learning disability is a descriptive concept, banding levels (Flint et aletal, 1995). Deletions becoming molecular medicine, andlittle not a disorder. A long held (and totally can be too small to detect by classical valid) view has been that the conditions methods (examples, include many of the escapes the grasp of modern . leading to severe and profound learning contiguous gene syndromes, where a micro- Most disorders associated with learning disability have identifiable pathologies, inclu- removes several genes), or large disability have at least a genetic ding genetic disorders. Mild to moderate enough to cause complete chromosome component influencing their expression; learning disability by contrast has been seen arm loss (e.g. cri-du-chatcri-du-chat) or whole chromo- in manydisorders, disturbances of genetic as largely sociocultural and multi-factorial/ some loss (e.g. Turner's syndrome). Other polygenic in origin. However, an increasing rearrangements can disrupt gene structure mechanisms play a pivotal role. number of single-gene conditions and directly or act by positional effects. Aims Dynamic , imprinting subtle chromosomal rearrangements that Familial disorders associated with lead to a mild to moderate outcome are learning disability often do not show simple mechanisms and gene^dosage effects are known, and it is important for people with Mendelian inheritance. Partial penetrance, explained with reference to genetic all degrees of learning disability that we dis- parent-of-origin effects and disorders thatleadthat lead to learning disability. cover as much as possible about the causal occur ± and in some cases (e.g. fragile-X) relationships involved. occur together. Advances in our under- MethodMethod A review of recent important standing of the molecular mechanisms studiesstudiesinthe in the genetics of learning disability. involved have been directly due to the study LEARNING DISABILITYAND of disorders associated with learning dis- ResultsResults A hostof new genetic GENETICS ability, adding important new concepts connections to conditions associated with such as dynamic mutations, imprinting learning disabilityhavedisability have been made. Our genome can be altered in many ways. and to human genetics The term `' usually implies change in general (the meaning of these terms will Conclusions A basic understanding of in the nucleotide sequence of single genes, be explained below). these genetic connectionsisimportantfor altering their coding information. Mutation The fact that there are more men than is one of three vital processes ± the others women with learning disability has been alllearning disabilitydisabilitypsychiatristsifthey psychiatristsifthey being recombination and random chromo- known for over a hundred years, and is are to follow the rapid changes ^ already some assortment at fertilisation ± that lead mainly due to X-linked disorders. The X beginning totoinfluence influence ourourpractice practice ^ that to the molecular individuality of a person. chromosome is also the best-studied human hold immense promise for the future. Mutations can be advantageous or harmful, chromosome, with detailed genetic maps depending on how they adapt the person available. It is unsurprising then that a Declaration of interest None. for a particular environment. Single nucleo- series of conditions associated with learning tide changes (point mutations) can be very disability has been regionally mapped to deleterious, especially if they occur in key the . Another major advance developmental genes. Point mutations in has been the generation of new animal the human eye±brain development gene models useful in studying the neurological `sonic hedgehog' can lead to the disastrous effects of gene mutations. The advent of outcome of holoprosencephaly. Mutations transgenics, with its ability to knock out in itsinits DrosophilaDrosophila larval counterpart lead specific genes or insert specific human to spiky outgrowths (hence the name). Such genes in (usually) the lab mouse, and to nomenclature now gives us desert, Indian, alter genes in targeted ways, has revolution- echnida, even tiggywinkle hedgehog genes ised our ability to correlate genotype and (Johnson & Scott, 1998). Many conditions phenotype. Using such methods, a sur- previously thought to involve large num- prising amount of information has been bers of genes (polygenic conditions) have gleaned about genetic conditions that now been shown to involve one gene or a produce learning disability. few major genes (oligogenic conditions), It would be impossible to cover, even {{See editorial pp.10^11, thisissue. and many seemingly unitary clinical superficially, all recent genetic findings.

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Instead, the focus will be on areas of the detection of specific genes producing gene. This gene immediately assumes a can- current interest that reveal how molecular specific clinical features, although some didate role in human brain development, genetics contributes to our understanding features may be due to the interactive although there will undoubtedly be other of the conditions associated with learning effects of different genes in triplicate rather genes in this region involved in neurological disability. The application of new methods than simply to increased dosage of single functioning. Such techniques should help to well-described conditions will centre on genes. Some of these partial trisomies lie the molecular dissection of other trisomies Down's syndrome, and dynamic mutations below the level of detection using classical and disorders with a suspected dosage will be illustrated by fragile-X, while on banding methods. An example is shown in effect.effect. the X chromosome several other key X- Figure 1.Figure1. Another genetic aspect of Down's syn- linked conditions associated with learning Animal models for Down's syndrome, drome, one that continues to throw up disability will be discussed. Mention will involving partial or full of the puzzles, is the association with dementia. be made of neuronal migration disorders animal chromosome syntenic for human The role of Alzheimer precursor protein located on , while the Prader± , have not always been con- (APP) is unclear, but some mechanism must Willi and Angelman syndromes will illus- vincing. Recently, however, transgenic mice exist to explain why pathology does not trate parent-of-origin effects, imprinting have been created with an excess of human usually appear until the third decade, even and uniparental disomies. Contiguous gene chromosome 21 material inserted into their though APP levels are persistently high syndromes will focus on genomes. By inserting different stretches of from foetal life. One suggestion is that an deletions, which may partly explain the human chromosome 21 DNA, the pheno- APP-scavenging mechanism fails with age, greatly increased rate of psychotic disorders typic effects of regional trisomy can be leading to plaques. The situation regarding in learning disability. Finally, there will be a explored (Smith et aletal, 1997). One such proposed modifying genes is also confused. brief discussion of where developments are mouse displaying specific learning deficits One finding is that the apolipoprotein ee44 leading in this field. was trisomic for a region containing the (APO-(APO-ee4) genotype may not have a direct human form of the Drosophila minibrain influence on the causation or course of

DOWN'S SYNDROME: NEW INSIGHTS INTO TRISOMIES

Down's syndrome is the paradigm of a (usually) non-inherited genetic disorder, where the effects are thought to be due to an excessive level of gene transcription (the dosage effect). To the psychiatrists its clinical presentation should need no description. The density of genes on a chromosome plays a large part in determining whether a foetus with a particular trisomy will survive to term, and the banded morphology of stained chromosomes is now thought to have a definite functional basis. Genes clus- ter in poorly staining R-bands, especially in early-replicating R-bands termed T-bands. Certain chromosomes, such as 19, are very T-band rich, others of comparable size such as 18 are comparatively gene poor. The three most survivable trisomies (21, 13 and 18) are precisely those with the lowest chromosomal gene densities. An average chromosome, however, will contain about 4000 genes; even a very fine chromosome band of 3 000 000 base pairs (3 Mbp) may contain over 100, and almost certainly Fig. 11Fig. Blackandwhitereproductionofchromosome21fluorescentBlack and white reproduction of chromosome 21fluorescent in situinsitu hybridisation (FISH) painting on a one of relevance to brain function. Gene clustering is relevant to the concept of a metaphase from a patient with clinical Down's syndrome but with no abnormality on classical karyotyping.karyotyping.FISH FISH critical region for a condition. Rare indivi- was performed using a commercial flow-sorted whole chromosome 21paint library conjugated with biotin, duals have chromosome 21 material in counterstained with 4,6-diamidino-2-phenylindole. Backgound and repeat sequence binding was eliminated partial trisomy through a duplication or using total human cot-l DNA and human ribosomal DNA.The chromosome banding pattern can been seen, as an unbalanced reciprocal translocation. can the signal on chromosomes 21.There is also an interstitial band of chromosome 21 signal near the centro- Relating the gene content of this excess mere of , which represents the small partial trisomy in this patient. An interphase nucleus (also material to clinical phenotype may help showing chromosome 21hybridisation) is present above of the metaphase.

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Alzheimer's disease, but may instead influ- from the paternally derived chromosome one copy of a gene ± that inherited from a ence the age at which the disease is likely 15. A deletion on the paternally derived particular parent ± is activated or repressed. to occur or progress (Meyer et aletal, 1998).,1998). silences these genes, and It is an epigenetic mechanism of controlling This finding may be relevant to age of onset Prader±Willi syndrome results. No single- gene expression, since the underlying DNA in Down's syndrome, where recent findings gene mutations that produce Prader±Willi sequence is not in itself disturbed and the indicate that individuals may be clinically syndrome have been found; the syndrome changes are potentially reversible. One spared ± if they live long enough, dementia is likely to be a true contiguous gene way to form an imprint is by the enzymatic will develop. syndrome involving several genes. In addition of methyl groups to nucleotides in the situation seems the DNA sequence. The classical instance simpler. Again, deletions predominate is the large-scale methylation and packaging PRADER ^ WILLI AND (causing about 70% of cases) but this time of the second X in women. However, ANGELMAN SYNDROMES : on the maternally derived chromosome 15. specific differential methylation patterns of DELETIONS,UNIPARENTAL One gene, UBE3A coding for E6-AP- restricted regions of autosomal DNA are DISOMIES AND IMPRINTING ubiquitin protein ligase, is expressed from well known, and the clustering of genes that MECHANISMS both chromosomes in most tissues, but are methylated on one chromosome but not preferentially from the maternally derived the other (as happens in the Prader±Willi Prader±Willi syndrome, although not chromosome 15 in the human brain. Single syndrome/Angelman syndrome region) common (one in 10 000±20 000 live births), point-mutations in this gene produce full suggests a functional relationship between has gained a number of notable firsts: it is clinical Angelman syndrome, and it may the different genes of the group. To the first human therefore be a true single gene disorder, establish a parent-specific imprint, in the found by high-resolution banding, the first although other genes may modify its first place the imprint from the previous human disorder where imprinting has been expression (Jiang et aletal, 1998).,1998). generation must be cleared in the parents' shown to play a critical role, and the first Another mechanism producing Prader± germ-line. The imprint is removed from human condition where uniparental disomy Willi syndrome (30%) and Angelman syn- both chromosomes of the pair early in contributes to its genesis (Cassidy, 1997). It drome (5%) is uniparental disomy. Here, germ-cell development; later (perhaps also is the paradigm of a behavioural both chromosome 15s have apparently de- around or even after birth), parent-gender- phenotypephenotype with developmental delays rived from one parent alone. A trisomy will specific differential methylation occurs. leading to variable degrees of learning dis- contain two chromosomes from one parent Methylation of DNA sequences may alter ability, hyperphagia with severe obesity, and a third from the other. If one chromo- (usually suppress, sometimes enhance) the hypogonadism and mild dysmorphic fea- some is lost the complement reverts to a binding of transcription or other factors tures such as small hands and feet and short disomy, and in one-third of cases this will controlling gene expression. Most human stature. The study of such behavioural contain two chromosomes from the samesame genes (about 60%) reside under CpG phenotypes, where specific reproducible parent. Another (rarer) mechanism could islands ± stretches of DNA enriched in C constellations of behaviours are assumed be a that is followed by duplica- and G dinucleotides. Methylation of these to be conditional on an underlying common tion of the chromosome. In the case of twotwo islands usually silences the relevant genes, genotype, is becoming an important dis- chromosome 15s arising from the mother, and CpG stretches are common in differen- cipline in itself. In Angelman syndrome there would be a functional silencing of tially imprinted regions. In the Prader±Willi (which affects one in 30 000 newborn paternally expressed gene, resulting in syndrome/Angelman syndrome region, one babies), moderate to severe learning dis- Prader±Willi syndrome. Similarly, if both paternal-chromosome expressed gene, ability is associated with an ataxic gait, chromosomes originated from the father a SNRPN, is very tightly regulated by methy- paroxysmal laughter, minimal speech, hand functional silencing of maternally expressed lation, so that its promoter region and flapping and seizures. genes would lead to Angelman syndrome. associated CpG island are completely The usual cause (70%) of Prader±Willi Uniparental disomy is usually detected by differentially methylated in all somatic syndrome is a microdeletion at chro- testing chromosome-15-specific polymor- tissues. Its main product is a nuclear-ribo- mosome 15q11-q13. The breakpoints are phic markers on DNA from the person with nucleoprotein-associated polypeptide. Tiny relatively stable and define a region about Prader±Willi syndrome or Angelman syn- microdeletions in the immediate vicinity of 4 Mbp in length. Although the micro- drome and both their parents. There is the SNRPN gene have been shown to alter deletion is just visible on high-resolution some evidence that the facial features of the methylation pattern of the Prader±Willi banding, the diagnosis is now usually based Prader±Willi syndrome caused by uniparen- syndrome/Angelman syndrome region and on FISH. Detailed mapping using rare tal disomy are less prominent than those of cause the relevant syndrome to occur. Such familial translocations and other rearrange- Prader±Willi syndrome caused by deletion, imprinting `mutations' are rare (occurring ments has shown that the critical regions so the degree of gene silencing may differ. in under 5% of the sufferers of either syn- for Prader±Willi syndrome and Angelman Studying why such genes are only drome), but point to the existence of an syndrome abut one another but do not expressed from a paternally or maternally imprinting centre involved in imprint overlap; the latter's critical region is more derived chromosome has shed much light establishment. Imprinting mutations lead- telomeric (closer to the end of the chromo- on the control of gene expression and has ing to Angelman syndrome lie centromeric some). In the normal person the Prader± revealed a completely new variety of mol- to those causing Prader±Willi syndrome, Willi syndrome region is known to contain ecular disorder ± imprinting centre muta- and both lie just centromeric to SNRPN, at least seven gene sequences (including tions. (Consta(ConstanciaÁncia etet suggesting that the imprinting centre may the neuronal necdin gene) solely expressed alal, 1998) is the mechanism by which only have two functional parts, one relating to

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a paternal-to-maternal imprint switch and by an X chromosome inactivation centre increased susceptibility, not a 100% risk the other to a switch in the opposite direc- (Xic). Within the Xic is a gene termed Xist, for a disorder ± is common. Sometimes tion. In the case of mutations producing encoding an untranslated structural RNA the disorder is more severe in the younger Angelman syndrome, the critical part of that coats the X chromosome, which is then generations of a family ± a phenomenon the imprinting centre actually overlaps the inactivated. The X chromosome seems to termed anticipation (historically, this term SNRPN gene, and certain exons of SNRPN be rich in inactivation promoting signals, meant an earlier age at oneset; its present in this region encode a transcript with a but inactivation will spread in a patchy connotation is more general). In other cases function different from that of its main tran- fashion across any translocated there is a dependence on whether the dis- script. Whether this is involved in imprint onto it. The active X chromosome does order is inherited through the male or formation is uncertain, but it shows expres- not express the Xist RNA, whereas the female germ line (the parent-of-origin sion specific to the paternally derived chro- inactive X chromosome continues to do effect). Most of our understanding of such mosome in the normal brain. The Prader± so. Xist gene deletions completely prevent patterns has come from the study of specific Willi syndrome imprinting centre also over- inactivation, but DNA deletions in the forms of learning disability, and one laps the SNRPN gene promoter, giving this immediate vicinity of the Xist gene cause essential step was the discovery of a gene a possible accessory role in both types non-random inactivation on the deletion dynamic unstable repeat element and asso- of imprint switch. Some imprinting centre chromosome only (Clerc & Avner, 1998). ciated gene (FMR-1) underlying fragile-X microdeletions are inherited. In Prader± Such sequences may be important in the syndrome.syndrome. Willi syndrome the patient has an imprint- counting process, in which inactivation Fragile-X is a relatively common cause ing centre mutation on the chromosome occurs only if there are two or more Xics of learning disability (affecting about one 15 derived from the father. The father is (this maintains X chromosome activity in in 4000 men and one in 8000 women); it phenotypically normal but has the imprint- Turner's syndrome). It would be interesting shows anticipation, the parent-of-origin ing centre mutation of the chromosome 15 to study Xic effects in other sex chromo- effect, and a very low apparent penetrance derived from his phenotypically normal some anomalies. XXX, XXY and XYY compared with other X-linked disorders. mother, who also has a microdeletion (pre- are relatively common (about The phenotype is variable, the most consis- sumably arising de novodenovo here). From the one per 1000 live births for each). Subjects tent features being learning disability and, patient's point of view, both chromosome with Klinefelter's syndrome and XXX have in affected men, macro-orchidism. Before 15 regions are maternal in their imprint lowered mean IQs; many therefore fall into the discovery of the gene, diagnosis rested and there has been a failure of imprint the learning disability range. The X chro- on phenotype, family history, and a karyo- switching in the father. In inherited Angel- mosome is unusual in that most of its genes type artefact ± a constriction at Xq27.3 (a man syndrome imprinting mutations, the show hemizygous expression (from only fragile site now termed FRAXA) in a per- opposite holds true. one chromosome). However, at least 20 centage of metaphases when the culture Three type A gg-aminobutyric acid genes, scattered throughout the short and medium is deprived of folate. The degree

receptor (GABAAA) genes occur in the telo- long arms, escape inactivation; the spread- of learning disability is usually moderate meric part of the Prader±Willi syndrome/ ing inactivation must therefore recognise in affected men and more variable in Angelman syndrome region. Their imprint- regional or individual gene environments. women; a mild degree may also exist in ing status is uncertain, but deletion of one A number of such genes cluster in one some female carriers. (GABRB3) has been said to increase the pseudo-autosomal region on the tip of the A stretch of DNA composed of a re- severity of epilepsy associated with short arm, and another near the tip of peated triplet of nucleotides (CCG) exists Angelman syndrome (Jiang et aletal, 1998),,1998), the long arm. These regions show recombin- in the 55inthe '' -untranslated end of the FMR-1 and duplications of the area have been im- ation within XX or XY pairs, and genes gene. Men affected with fragile-X have a plicated (Schroer et aletal, 1998) in some cases here are functionally expressed from both large expansion of 230±1000 or more of autism. The incidence of psychosis in X and Y chromosomes. Hence, any clinical triplets. The cytosine residues of CG base adults with Prader±Willi syndrome (5%) phenotype in sex chromosome polysomies pairs are highly methylated here and in is raised relative to the general population is presumably due to dosage effects of the surrounding DNA areas, including the rate, and it would be important to see duplications of the pseudo-autosomal and CpG island/promoter region essential to whether these people also had changes in other genes that escape silencing. Indeed transcription factor binding ± hence the their GABA receptors. (excluding the fairly common karyo- gene is silenced. Rare individuals with spe- types with two or more independent cific deletions or silencing point-mutations clonal cell lines), the higher the sex chromo- of FMR-1 have full clinical fragile-X, indi- THE X CHROMOSOME AND some count, the greater the degree of learn- cating that disruption of FMR-1 alone is ITS DISORDERS ing disability (in, for example, enough to produce the condition. With and pentasomy X). These conditions are the dynamic mutation it is the methylation Gender-linked disorders are very important an obvious target for future molecular that is important rather than any direct in learning disability, and the X chromo- study.study. effect on gene transcription, since unusual some has been the most studied part of all enzyme defects that prevent gene methyla- the human genome. tion do not result in fragile-X even if a full Only one X chromosome must be Dynamic mutations expansion is present. Furthermore, experi- fully active at one time in any diploid cell. Many inherited disorders do not obey mental demethylation of the gene restores Inactivation of the second X chromosome Mendel's rules. Variable penetrance ± full transcriptional activity (Chiurazzi etet in women is a random process, controlled wherebywherebygenegene disruption confers an alal, 1998).,1998).

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In the general population the repeat Protein) with the widespread tissue distri- establishment or synaptic connections, by consists of 6±50 triplets (mean 30). These bution that may play a role in cellular complex cellular signalling mechanisms can be passed on from one generation to mRNA transport. The highest FMRP levels involving diffusible factors or direct cell± the next without phenotypic consequences occur in the brain (in the cortex and espe- cell contacts. An important set of proteins or change in their size. Triplets are mainly cially the cerebellum) and testes. The brain mediating the latter is the L1 group of CGG nucleotides, but about one in 10 is in fragile-X shows increased size of the neural cell adhesion molecules. Structurally AGG. A relative lackof AGG sequences hippocampal and caudate nucleus and resembling immunoglobulins, these mol- (increasing the run of `perfect' CGG decreased size of the posterior cerebellar ecules act as both adhesion molecules and triplets) or an increase in the number of vermis. The latter may also be reduced in signalling receptors. Human L1 gene again CGG triplets towards the 3'' end of thetheendof some people with autism, and links be- lies on the X chromosome (Xq28); muta- sequence introduces length instability, in- tween the conditions have been postulated. tions cause a wide spectrum of important creasing the riskof a small expansion in The repeat's population genetics has neurological conditions, often with severe size when passed on in the normal popu- also been studied. In some populations learning disability. The first association lation. This may be one source of a slow (e.g. in Scandinavia) the new mutation fre- made was with X-linked hydrocephalus, increase in the size of small repeats in the quency is low, with evidence for an ances- but mutations in the samesame gene can cause general population. In the families of tral founder mutation, a feature unusual complicated spastic paraparesis (type 1), fragile-X patients the situation is different. in an X-linked condition. In the UK the corpus callosum agenesis, and MASA `Premutations' of 60±200 triplets occur in haplotype diversity is wider, with less (mental retardation±aphasia±shuffling gait± the mothers and in men who must be trans- evidence for a founder effect. Such popu- adducted thumbs) syndromes. These have mitting the disorder (`normal transmitting lation differences in origin and carriage been grouped under the acronym CRASH males'). When transmitted by a mother to may imply that different processes are syndrome (corpus callosum, mental retar- her child, these premutations are unstable responsible for the upward creep in size. dation, adducted thumbs, spastic para- and almost invariably undergo a large A large Canadian study (Rousseau et aletal,, plegia, hydrocephalus). Over 85 different expansion (further CGG triplets are 1995) found repeats of 66 or more triplets mutations have been described in this gene added). Smaller premutations may expand in one in 500 women and a similar fre- alone, and the particular type of mutation by maternal transmission to large premuta- quency for 55±63 triplet repeats, and indi- relates to clinical outcome (Fransen et aletal,, tions, and large premutations may expand cated that around one in 2900 children 1998). Coding region mutations in the to the very large mutation seen in indivi- should carry the mutation. Detection and extracellular domain of L1 cause truncation duals with full fragile-X. Like the normally sizing of the repeat are now carried out or absence of the protein, leading to an sized repeat, the breakage of a pure run of on DNA extracted from a venous blood extreme phenotype (severe hydrocephalus, CGGs by AGG stabilises the premutation sample, but many subjects (particularly old- profound learning disability, often early (and is another source of variance in the er men with learning disability) remain un- mortality). Cytoplasmic domain mutations, clinical counselling of this condition). classified, correcting this will be important, by contrast, may only cause partial loss of The conversion of an unstable pre- especially if the subjects have phenotypic functioning and a much milder, variable mutation into a large expansion by passage features or a family history. disorder without ventricular dilatation. through a female meiosis causes the parent- Around 12 other dynamic mutations The clear relationship between genotype of-origin effect. The mechanism of the are known (Richards & Sutherland, (mutation position within the gene struc- expansion is uncertain, but interestingly it 1997). The X chromosome (Xq28) fragile ture) and clinical phenotype is fascinating is not present in the sperm of men with full site FRAXE harbours a CGG repeat whose but does not allow us, in itself, to under- fragile-X. Either the germ line is protected expansion and associated gene silencing stand the developmental pathways involved from full expansion, or sperm with the ex- (FMR2 ± the protein is expressed in the in the different outcomes. However, mouse pansion are selectively eliminated, or there human brain, including the hippocampus) models with complete knock-out of the L1 is a true regression in size of the expansion. produce mild learning disability or specific gene correspond to severe phenotype muta- Workfrom Oostra's group (Matter et aletal,, educational problems. However, the repeat tions (Kamiguchi et aletal, 1998), and targeted 1997) favours the last explanation, the in this case can expand or contract on mutagenesis should allow the creation of further study of which may help us to transmission. Dynamic mutations need specifically altered L1 genes that model understand the mechanisms involved in not be restricted to triplets. A common the other phenotypes. changing an expansion's size. Whichever polymorphic repeat of 33 bp is found in explanation is correct, there must be some FRA16A, so far without an associated imprinting mechanism specific to female clinical phenotype; and many more prob- The non-syndromic X-linked transmission that differentiates a premuta- ably remain to be discovered. conditions: one clinical condition, tion from a normally sized repeat. Further- many genes more, in fragile-X there is high incidence of Many families with multiple individuals somatic cell mosaicism for both full muta- The L1-associated conditions: one affected by learning disability seem to fit tions, and premutations, and the premuta- gene, many clinical conditions into an X-linked inheritance pattern. tion-carrying cells are transcriptionally The genetics of learning disability is the Nevertheless, imaging and other investiga- active, making exact genotype±phenotype genetics of neurodevelopment. Developing tions show that gross anatomical brain correlations very difficult. The FMR-1 mu- neurones are controlled and guided in their development in these individuals is indistin- tation produces an RNA binding protein physical migrations, in their axon and den- guishable from that of the normal popu- (FMRP, Fragile-X Mental Retardation drite tree spreading, and in the eventual lation, and there are few symptoms other

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than learning disability. Clinically, these both chromosomes, the effect is due to a subtle chromosomal changes has been conditions are homogeneous, and they have reduction in protein level rather than unveiled, along with an increasing number earned the title of `non-syndromic X-linked absence. A mouse hemizygous knockout of interstitial microdeletion and duplication mental retardation'. Sufferers form an model has been created and has thrown syndromes producing contiguous gene syn- important subset of people with learning light on many aspects of neural migration dromes. Many of the latter have a related disability (0.3% men), and behind the clin- (Hirotsune(Hirotsune et aletal, 1998), but does not show learning disability, while all involve the ical similarity lies a great deal of genetic the severe Miller±Dieker syndrome cortical disruption of a series of grouped genes by heterogeneity. FRAXE (see above) was the phenotype, serving to remind us that mouse the abnormality. Prader±Willi syndrome is first such condition to be understood, but is not always akin to man. Another (X a contiguous gene syndrome that shows several other non-syndromic X-linked men- chromosome) lissencephaly gene produces imprinting effects, as does Beckwith± tal retardation genes have now been found. the protein doublecortin, which may act Weidemann syndrome (duplication of One gene (GD11, Xq28) may modulate on migration through intracellular calcium- 11p15). Most contiguous gene syndromes exocytosis during synaptic transmission. A dependent signalling (Sossey-Alaoui et aletal,, are deletions with reductions in gene second gene at Xq12 produces a protein 1998). Clinically its effect is very similar dosage (haploinsufficiency); examples are (unfortunately) labelled as oligophrenin to Miller±Dieker syndrome. Miller±Dieker (17p13.3), Langer±Giedon (Billuart(Billuart et aletal, 1998). The clue to finding (8q24.1) and Rubenstein±Taybi (16p13.3) this gene was a female with mild learning syndromes.syndromes. disability with a t(X;12) balanced recipro- cal translocation where the breakpoint Microcephaly is an extremely hetero- had disrupted the gene's intron/exon struc- geneous clinical condition, with a variety The diGeorge and velo-cardio- ture. Different loss-of-function mutations of intrauterine toxins, infections and birth facial syndromes in this gene were found in other unrelated asphyxia being implicated in individual These clinically overlapping disorders are individuals. The protein, a rho-GTPase, cases. However, true recessive micro- associated with a microdeletion at chromo- may influence signalling during cell migra- cephaly is an autosomal-recessive disorder some 22q11 that can be detected using tion and axon±dendrite outgrowth. Most presenting simply with microcephaly and FISH. They are frequent conditions (one recently, a series of brain-expressed genes learning disability without other severe in 4000 live births) occurring, for example, has been identified within Xq21-q24 ± neurological features. It has been analysed in 5% of children with congenital heart one of which, PAK3, is mutated in all in two consanguineous kindreds by a defects. The pattern of anomalies suggests affected males in a family with non- whole-genome linkage scan using the abnormal movement of neural crest cells syndromic X-linked mental retardation, method of homozygosity mapping (Jackson that migrate into the embryonic pharyngeal with carrier females being heterozygotes et aletal, 1998). In essence, data are obtained arches. DiGeorge syndrome is associated (Allen(Allen et aletal, 1998). The PAK3 protein, also from a large number of closely spaced poly- with micrognathia, cleft palate, low-set part of the rho-GPTase signalling chain, is morphic markers covering all chromo- ears, , short palpebral fissures highly expressed in the developing cerebral somes, and identical stretches of marker and major cardiac abnormalities. Velo- cortex and hippocampus. It is certain that allelles (haplotypes) that are present on cardio-facial syndrome is extremely vari- many more genes will be discovered, each both chromosomes of a pair are identified able (symptoms include midface under- with its own different set of mutations. in affected individuals. Recessive disorders development, bulbous nose, cleft palate, require disruption of genes on both chro- neonatal parathyroid and thymus pro- mosomes of a pair, the smallest interval of blems, and conotruncal cardiac abnormal- such two-chromosome haplotype-identity AUTOSOMES AND ities), but has a fairly consistent mild shared between different affected family DISORDERS OF learning disability. The variability occurs members defines the region proposed to NEURODEVELOPMENT between individual sufferers and even with- harbour the gene of interest, in this case in the same family. Deletions with different The lissencephalies: disorders of on chromosome 8q. breakpoints have helped to define the criti- neuronal migration cal region of 480 kbp, from which seven Brain sulci and gyri are underdeveloped in CONTIGUOUS GENE genes have so far been isolated; the latest, many syndromes associated with learning SYNDROMES: DISORDERS which is expressed in many human tissues disability, such as Down's syndrome. How- OF MANY GENES AT ONCE including foetal and adult brains and head ever, the most striking degree of under- and neck(Funke et aletal, 1998), is a key development occurs in the lissencephalies FluorescentFluorescent in situsituin hybridisation (FISH) candidate for neuropsychiatric effects. (the `smooth brains'), where arrested neu- methods, where a DNA probe(s) is directly There has recently been interest in the ronal migration in which the normal six- or indirectly coupled to a fluorescent association between these syndromes (and layered folded cortex does not develop reporter element, have revolutionised karyo- 22q11 deletions) and the riskof develop- leads to a profound degree of learning dis- typing.typing.The previous resolution limit with ing schizophrenia and learning disability ability. One human lissencephaly gene high-resolution banding was about 3 MbP; (Murphy(Murphy et aletal, 1998). Deletions have been (the unpronounceable PAFAH1B1 on chro- FISH can detect much smaller changes claimed in one in 40 of those with both mosome 17p) is disrupted by a hemizygous (one method ± fibre FISH ± teases out diagnoses and in one in 200 of those with microdeletion in Miller±Dieker syndrome. uncoiled interphase chromosomes and can schizophrenia alone. Independent studies Since the deletion is on one chromosome detect differences in composition at the have also suggested linkage between poly- only and the gene is usually expressed from kilobase level). A whole series of new and morphic DNA markers in this region and

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familial schizophrenia. The fact that the point-prevalence of schizophrenia in people CLINICAL IMPLICATIONS with mild learning disability is three times that of the general population is well && Genetic advances have revealed the molecular underpinnings of many conditions known, and comorbid subjects have re- associated with learning disability.New diagnostic groupings based on genotypes will cently been shown to have a striking inci- place developmental and clinical studies on a firmer biological basis. dence of family history, with a very variable phenotype in relatives (Doody etet && High-throughput molecular diagnostics will allow the screening of large numbers alal, 1998). Thisfamiliality is unexplained, of individuals for learning disability conditions in future. but chromosome abnormalities such as del(22) that co-associateco-associate with the condi- && The understanding of molecular mechanisms is likely to help the development of tion may provide important clues in the better targeted interventions and possible therapies. search for genes. In fact, chromosome ab- normalities havebeen pointers to the loci LIMITATIONS for genes for many genetic diseases, and && It has not been possible to cover all genetic conditions and mechanisms associated the case isstrengthened where there is with learning disability in this review. additional independent evidence of linkage of the condition to the abnormal chromo- && Even with the advent of transgenics, animal genetic models do not always mirror some. One such case occurs where two the human condition. separate families (Mors et aletal, 1997) segre- gating a pericentric inversion (18) with phe- && The rapid advances in understanding genetic mechanisms have not been matched notypes of psychotic illness and learning by comparable developments in our thinking about ethical and moral issues. disability have breakpoints at the two loci with strong independent evidence of linkage to both bipolar disorder and schizophrenia. WALTERJ. MUIR,MRCPsych, Department of Psychiatry,University of Edinburgh, Kennedy Tower, Royal Edinburgh Hospital, Morningside Park, Edinburgh EH10 5HF THE FUTURE (First received 12 July 1999, final revision 15 September 1999, accepted 16 September 1999)

The polymerase chain reaction (PCR), a now well-established method, has changed the face of molecular genetics, allowing interest in chip technology techniques REFERENCES the specific amplification of DNA from tiny is high and looks set to revolutionise amounts of material, and has facilitated the molecular diagnostics. Allen, K. M., Gleeson, J. G., Bagrodia, S., et aletal (19 9 8) international human genome sequencing We also need a revolution in our ethical PAK3 mutation in nonsyndromic X-linked mental retardation. Nature Genetics,, 2020, 25^29.,25^29. effort. This project is generating massive thinking about the implications of these quantities of new gene sequences that are changes. To ignore advances would be Billuart, P., Bienvenue, T., Ronce, N., et aletal (19 9 8) Oligophrenin-1 encodes a rhoGAP protein involved in candidates for conditions underlying learn- therapeutic nihilism; however, moral and X-linked mental retardation. Nature,, 392, 923^926.,923^926. ing disability. Methods permitting the eco- legal safeguards for patients and their nomic screening of thousands of these families are urgently needed, as the pace Cassidy, S. B.(19 (1997) 9 7) Prader^Willi syndrome. Journal ofofJournal ,, 3434,,913^923. 913^923. genes are being devised. DNA chip-based of change is extraordinary. There is indeed assay is an emerging technology in which a danger of creating a `new eugenics', and Chiurazzi, P., Pomponi, M. G.,Willemsen, R., et aletal (19 9 8) In vitroInvitro reactivation of the FMR1 gene involved gridded microarrays of thousands of the lessons of Hadamar should never be in . Human Molecular Genetics,, 77,, DNAs, cDNAs, PCR products and other forgotten. All learning disability psychia- 109^113. nucleotide sequences can be attached to trists should read the report of the Nuffield Clerc,Cl e r c , P. & Avner,Av n e r, P.(19 (1998) 9 8) Role of the region 3'' to XisttoXist small pieces of glass or silicon and analysed Council on Bioethics (1998), where all exon 6 in the counting process of X-chromosome for hybridisation matches with patient sam- issues, including insurance, employment inactivation. Nature Genetics,, 19, 249^253.

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