Human Molecular Genetics, 2006, Vol. 15, Review Issue No.

2 R110–R116

The genetics of mental retardation
F. Lucy Raymond1,* and Patrick Tarpey2
Department of Medical Genetics, Cambridge Institute of Medical Research, University of Cambridge, Addenbrookes
Hospital, Cambridge CB2 2XY, UK and 2The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus,
Hinxton, Cambridge CB10 1SA, UK

Received July 3, 2006; Revised July 14, 2006; Accepted July 25, 2006

Genetic abnormalities frequently give rise to a mental retardation phenotype. Recent advances in resolution
of comparative genomic hybridization and genomic sequence annotation has identified new syndromes at
chromosome 3q29 and 9q34. The finding of a significant number of copy number polymorphisms in the
genome in the normal population, means that assigning pathogenicity to deletions and duplications in
patients with mental retardation can be difficult but has been identified for duplications of MECP2 and
L1CAM. Novel autosomal genes that cause mental retardation have been identified recently including
CC2D1A identified by homozygosity mapping. Several new genes and pathways have been identified in
the field of X-linked mental retardation but many more still await identification. Analysis of families where
only a single male is affected reveals that the chance of this being due to a single X-linked gene abnormality
is significantly less than would be expected if the excess of males in the population is entirely due to X-linked
disease. Recent identification of novel X-linked mental retardation genes has identified components of the
post-synaptic density and multiple zinc finger transcription factors as disease causing suggesting new
mechanisms of disease causation. The first therapeutic treatments of animal models of mental retardation
have been reported, a Drosophila model of Fragile X syndrome has been treated with lithium or metabotropic
glutamate receptor (mGluR) antagonists and a mouse model of NF1 has been treated with the HMG-CoA
reductase inhibitor lavastatin, which improves the learning and memory skills in these models.

INTRODUCTION Down syndrome as a chromosome abnormality, the focus of
mental retardation research has been to identify smaller and
The genetic basis of mental retardation is now a huge field smaller chromosome abnormalities associated with disease
having started with modest beginnings with an initial survey (2,3). The aim is to understand the molecular basis of intellec-
of patients confined to long stay hospital institutions in the tual disability and to provide an ever-improved clinical service
1930s (1). This review has concentrated on the most recent pub- to this group of patients and their families. In the early days,
lications that advance the field rather than attempting to be an the identification of gain or loss of genetic material on routine
exhaustive summary. The review begins with recent work on chromosome analysis at a 500 G banding resolution was
genomic deletions and duplications and progresses to new usually clinically significant as a karyotype was in effect a
single gene abnormalities that have been identified. A broad visual inspection of the whole genome at the resolution of
overview of the classes of genes that give rise to mental retar- 5– 10 Mb. Gain or loss of 5 –10 Mb of DNA represents a
dation are discussed and reference is made to the first two large footprint of genes wherever the abnormality is found
papers suggesting possible therapies for defects in learning in the genome and almost inevitably leads to developmental
and memory in animal model systems of the disease. abnormalities during embryogenesis. The most common
effect of a chromosome abnormality is cognitive impairment,
but it is also frequently associated with defects of heart for-
LARGE CHROMOSOME ABNORMALITIES mation and dysmorphic features. Occasionally, rare variants
A genetic aetiology for mental retardation has been recog- are described with no clinical significance and are usually
nized for many years and since the first identification of associated with variations of euchromatic material (4).

*To whom correspondence should be addressed. Tel: +44 1223762609; Fax: +44 1223331206; Email:

# The Author 2006. Published by Oxford University Press. All rights reserved.
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Recent publications have estab- logical significance would not have been possible and other lished that a further 10% of patients with mental retardation duplications of genes in Xq28 have not necessarily been associ- carry deletions or duplications (14. Cri du Chat. Human Molecular Genetics. in a single or few procedures.25). These were only detectable by fluor- 97% of patients had a reproducible copy number change and escence in situ hybridization (FISH) or similar techniques on average each patient had three detected changes throughout and include the common microdeletion syndromes of: Wolf- the genome. Prader-Willi. Williams. 2006. the technology has been further developed to identify the X chromosome at Xp22. therefore thought to be polymorphisms or were unproven as Rubinstein-Taybi. The use of multiple probes sim- Without previous identification of point mutations in L1CAM ultaneously is now possible using probes of known location on and MECP2 this assignment of a duplication in Xq28 to patho- the genome 1 Mb apart (13). This reflects a more predispose to disease is now under close scrutiny (24.19). there are many single gene disorders ial polymorphic deletions or duplications were noted making where deletions and duplications are common causes of disease the clinical significance of a deletion in an individual with e. the task is to identify which features are associated COPY NUMBER CHANGES with a large deletion and which are only due to haploinsuffi- With further development and refinement of array CGH tech. Clinically. a pathological duplication of MECP2 and L1CAM Having established the principle that small deletions or has been described in males with severe mental retardation and duplications of chromosome material can lead to mental retar- progressive neurological symptoms but other duplications on dation. Although there appears to be a high degree of selection bias Once a significant number of screens of telomeres were per- against copy number changes in regions of the genome where formed in individuals with mental retardation.15). however.27). More recently. in the population and likely to be due to a single gene or a In 1995. Although the genomic coverage of this each syndrome has characteristic distinguishing features all are form of tiling path is a great improvement on the 1 Mb array. Flint et al. general trend that classification of mental retardation syn- dromes associated with fine chromosomal abnormalities is increasingly based on molecular similarities (recurrent similar deletions or duplications) based on grouping of clinical COPY NUMBER CHANGES IN SINGLE GENES dysmorphology features alone. Initially. also associated with varying degrees of mental retardation and the issue of deciding whether or not a rare variant is disease- in some cases associated with specific areas of intellectual causing is now a major issue.3. Duchenne Muscular dystrophy. screening individuals It is emerging that the human genome is highly variable with minimal dysmorphic features but mental retardation as from one individual to another and large-scale copy number the predominant feature has resulted in the delineation of duplications or deletions within the genome are commonly several new microdeletion syndromes including 3q29 micro- polymorphic (18. stage these were relatively rare (8. Xq22. characteristic syndromes. of 2. the development has been on the X causes which of the phenotypic features. Where the phenotype is unusual impairment. Recently. For the recently chromosome. Angelman.29). selected for analysis were both dysmorphic and had significant The criterion for identifying whether or not a gene is patho- mental retardation.3 and Xq26.g. (5) extended this technique to develop a few single genes within the genome distinguishing copy strategy to screen for the abnormal inheritance of subtelomeric number changes that are pathological or polymorphic can be DNA polymorphisms in individuals with mental retardation relatively easily resolved. Smith-Magenis. these conditions are not and complex rearrangements are far more common than was easily united but the identification of a common microdeletion previously identified (20 –23) and the extent to which these forms the basis of the classification (11). 15. e. In this study. Initially.3 have also yet smaller deletions and duplications in the whole genome been described with no pathological significance (28.12).9. For some microdeletion syndromes nology leading to more extensive coverage of the genome. For microde- letions associated with dysmorphic feature and mental retar- dation. as this chromosome is well annotated and a described 9q34 deletion syndrome. Furthermore. both parents were not available to confirm the origin of the Alagille. DiGeorge and 22q11 deletion syndrome. Since this initial observation screen- type is less distinct such as mental retardation and where the ing telomeres for deletions has become routine in clinical number of single genes that cause this phenotype is at service for suitably selected patients with a diagnostic yield minimum 100 and probably very many more. ciency of a single gene. Pelizeaus Merzbacher and mental retardation occasionally difficult to interpret but at this Charcot Marie Tooth disease (26. recurrent small microdeletions of the genome revealed that 10% had de novo abnormalities in a cohort of not visible by light microscopy were identified associated with mentally retarded individuals (17). 2 R111 MICRODELETIONS novel BAC tiling resolution genome-wide microarray has been successful and the use of this in a study of 100 patients In the early 1990s.g. Although copy number change. Vol. rare small famil- Mendelian disorders map. Most of these changes were either familial and Hirshhorn. those patients ated with disease (30). Miller-Dieker lissencephaly. but this is less easy when the pheno- and dysmorphic features.5 –15% (6 – 9). Review Issue No. are not found in appropriate control populations. Williams and 22q11 deletion syndrome it still has to be single gene abnormalities that result in mental retardation can fully resolved which gene in the common deleted region now be detected. the extent of inversions deletion syndrome (10). Further developments to generate a gantly identified by collecting a series of patients with smaller . The deletions that have been detected have logical is by identifying coding sequence abnormalities that been large and generally incorporating several genes. a single gene within the large number of X-linked mental retardation genes map to the commonly deleted region that causes the disease has been ele- X chromosome (16).

of a population by a founder mutation that will have occurred UK.sanger. it due to X-linked inheritance both due to the retention of is emerging that there are large numbers of unique rare variants X-linked genes in the population by the maintenance of being identified on the X chromosome in the cohort of 200 . ZNF81 (56) relied on the characterization of familial cases. SMCX the new mutation rate. 15.71). Support for the later features in order to analyse and group together.3) which has been assumed to be this major project has not reported its completed findings yet. This method is powerful for detecting auto- X chromosome that cause mental retardation. The Genetics of Learning Disability fication of rare families with the condition and the enrichment (GOLD) study was established by the authors in Cambridge. a novel systema- somal recessive genes that cause disease but require the identi- tic approach is needed. in the population and the large number of genes on the X ruption of a gene at a balanced translocation breakpoint is still chromosome that gives rise to the condition (1). have been found or much more likely that the remaining The identification of novel genes has relied on the collecting number of genes that are to be found and now increasingly dif- of individuals with mental retardation and distinct dysmorphic ficult to identify because of their rarity.12 have been ident- missense variants were identified (Raymond et al. Currently. Conditions like view is the presence of a large number of published and unpub- Smith-Magenis syndrome and Rubinstein-Taybi have been lished families with three or four generations affected with identified this way and the single genes that are sufficient to moderate to severe mental retardation and a clear X-linked cause the phenotype have been identified by systematic deletion inheritance patterns that have not had the causative mutation mapping and point mutation analysis (34. to identify novel genes that cause X-linked mental retar- by chance. Since 1990. (49). DLG3 (49). Families with the largest pedigrees are prioritized as disease in There is a male excess of affected individuals compared these is most likely to be due to a single gene defect. GDI (55). Where (74) and SLC16A2 (75 –77). ARX (64. the identification of based on sequence homology and functional similarity to these genes has been relatively slow. AGTR2 (67).54). it is usually effec- forms of mental retardation is described are NLGN4 (58).73). with mental retardation and are not reported to be associated causing gene (33). Although with females (ratio1: 1. ARHGEF6 (52). 2 and smaller deletions and identifying an apparently balanced reproductive fitness in females contributing to the prevalence translocation with the phenotype (31). PAK3 The identification of genes that cause disease have usually (51).uk). In order to identify the remaining genes on the families (36 –38).e. The anticipation is that many new genes will dation. PRSS12 on those that have already been identified in a panel of 300 chromosome 4q26. TM4SF2 (46). the use suggesting that yet more genes need identification. Demonstrating the dis. for autosomal dominant forms.44). Although region that included 50 genes in this region revealed only there are likely to be a significant number of genes on auto- three new genes.. FGD1 (72.35). whereas the genes where syndromic mental retardation is severe in the family. mental retardation without syn- In the past 18 months. The group is using high throughput genomic DNA emerge using this technique in the next 5– 10 years. FMR2 (53. A systema- of homozygosity mapping in highly consanguineous families tic but limited search of brain expressed genes within Xp11 with affected siblings has great potential power. ATRX (62). identified despite extensive screening of the known genes For autosomal recessive causes of mental retardation. tively a reproductive lethal mutation and therefore autosomal RPS6KA3 (RSK2) (59). The first insufficient to be confident that a particular gene causes gene to be identified was FMR1 that causes fragile X syn- disease as subtle gain or loss of genetic material in individuals drome and still remains the commonest single gene abnormal- with translocations and no phenotype have been described ity to be identified (39 –42). and a detailed screen of 70 candidate genes somes that cause mental retardation. Where the and ZNF674 (57). SYN1 (66). OPHN1 (60. The prevalence of diseased genes is therefore dependent of MECP2 (68 – 70). the number of newly identified genes dromic features. a series of genes have (32). The current estimate of genes to be screened is 854 (http://vega. Three genes. This gene now adds to the list of diseased with dysmorphic or other neurological symptoms and others genes where mental retardation is the predominant feature are more syndromic although the distinction between these with or without additional clinical or dysmorphic features. unpub- ified using autozygosity mapping of highly consanguineous lished) (78). SLC6A8 (63). Some are only associated 1 (EHMT1) has assigned this phenotype to a specific disease. FTSJ1 (48). The final identification of a point mutation in a single been identified either by positional cloning or translocation gene within 9q34 in euchromatic histone methyl transferase breakpoint mapping methodologies. 2006. the identification of these individuals is clini- has not increased exponentially despite technological advances cally difficult and thus the number of characterized autosomal suggesting that either nearly all the genes on the X chromosome dominant genes that give rise to mental retardation is low. PQBP1 (56.65). but it is sequencing of all coding exons of all genes on the X chromo- unlikely to reveal all autosomal recessive genes as it cannot some in a cohort of 200 X-linked mental retardation families provide a systematic method of surveying the genome. give rise to mental retardation are on the X chromosome. the phenotype is common are gradually becoming less clear as syndromic and non- syndromic phenotypes are described for several of the genes (43. which male individuals. a normal karyotype and no known diagnosis. and the number of primer pairs required for coverage is 7200. FACL4 (50). CRBN on chromosome 3p26 and most X-linked families only identified one novel gene where three recently CC2D1A on chromosome 19p13.61). Review Issue No. genes that are classified as non-syndromic CODING ABNORMALITIES IN SINGLE GENES mental retardation genes are: IL1RAPL1 (45).R112 Human Molecular Genetics. Vol. The criteria for selecting the X-LINKED MENTAL RETARDATION family for sequencing is the presence of at least two affected The majority of single genes that have been identified. dominant pedigrees are unlikely to appear in the population. ZNF41 (47).

1). II5. TEX13B NM_031273. II1. 2 R113 Figure 1. 2006. III6. the posing alleles need to be identified and are not necessarily identification of many further genes that cause X-linked located on the X chromosome. Human Molecular Genetics. from the rarer X-linked family pedigrees. Nevertheless. IV1 and IV2 were tested. Vol. III3.6% but was only 0. This polygenic model . This has important implications for the was high at 6. II3. For the family with a mutation in GPR119 individuals I1. 15. I2. The location of the mutations and the subsequent protein alterations are based on the following RefSeq sequences: GPR119 NM_178471. III1 and III2 were tested. For the family with a mutation in TEX13B individuals II1. III1 and III2 were tested. the observations of Mandel and Chelly polymorphic and not necessarily associated with the disease that the prevalence of mutations in ARX in X-linked pedigrees phenotype (Fig. II4. This be aware that de novo sequence variants are not necessarily suggests that in males there is a general predisposition to pathogenic if the phenotype under scrutiny is caused by a mental retardation akin to that of autism where genetic predis- large number of different possible genes. but may account for the mental retardation hopes to be a significant contribution to increased prevalence of disease in male sib pairs quite separate the field. NP_848566. II1. Sequence traces of genomic DNA from the probands are shown with the mutation indicated. III4. ATXN3L XN_045705. NP_112563. III2. For the family with a mutation in ATXN3L individuals I2. challenges molecular genetics community and emphasizes the need to the assumption that all male mental retardation is due to high have samples from distant relatives to track mutations and to penetrant abnormalities on the X chromosome (79). XP_045705. II4. II3. Probands are indicated by black arrows and individuals where mutation tracking was inconsistent are indicated by red arrows. Mutation analysis of families with X-linked mental retardation.13% in singletons. Review Issue No. II2. We In addition to the difficulty of finding mutations in large have evidence that truncating mutations are not infrequently X-linked families. families and not all of them are likely to be disease-causing.

Defect.J. Brunner.. Homfray. A. and immediate insights into the mechanism of the disease processes. 385–398. Acad. 2006. S. A. (2003) Telomeres: a diagnosis at the end of the chromosomes... M. Veltman. Hedrick.R114 Human Molecular Genetics. Although these observations are a far submicroscopic rearrangements associated with mental retardation..H.H. J. (2003) The use of telomere probes to investigate inhibitor lavastatin (83). 1676–1681. that our intellectual processing is both sophisticated and 3. Genet. Smeets. C.. Am.G. the possi. Cabanas.N. The genes identified earliest were frequently signalling molecules in the RhoGTPase pathway (GDI. A. J.. that cause mental retardation.. Martin. where free T3 levels are abnormality high and for SLC6A8 where urine and plasma creatine:creatinine levels are abnormal.. 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