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

2 R110R116
doi:10.1093/hmg/ddl189

The genetics of mental retardation

F. Lucy Raymond1,* and Patrick Tarpey2
1
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

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

*To whom correspondence should be addressed. Tel: +44 1223762609; Fax: +44 1223331206; Email: flr24@cam.ac.uk

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 Human Molecular Genetics, 2006, Vol. 15, Review Issue No. 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, 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). In this study, however,
characteristic syndromes. 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. Most of these changes were either familial and
Hirshhorn, Cri du Chat, Williams, Prader-Willi, Angelman,
therefore thought to be polymorphisms or were unproven as
Rubinstein-Taybi, Miller-Dieker lissencephaly, Smith-Magenis,
both parents were not available to confirm the origin of the
Alagille, DiGeorge and 22q11 deletion syndrome. Although
copy number change. 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,
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. Where the phenotype is unusual
impairment.
in the population and likely to be due to a single gene or a
In 1995, Flint et al. (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, but this is less easy when the pheno-
and dysmorphic features. 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.
of 2.5 15% (6 9). More recently, 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 (18,19). Furthermore, the extent of inversions
deletion syndrome (10). Clinically, 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). This reflects a more
predispose to disease is now under close scrutiny (24,25).
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.
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, rare small famil-
Mendelian disorders map, 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.g. Duchenne Muscular dystrophy, Pelizeaus Merzbacher and
mental retardation occasionally difficult to interpret but at this
Charcot Marie Tooth disease (26,27).
stage these were relatively rare (8,9,12).
Recently, 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, the technology has been further developed to identify
the X chromosome at Xp22.3, Xq22.3 and Xq26.3 have also
yet smaller deletions and duplications in the whole genome
been described with no pathological significance (28,29).
in a single or few procedures. 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). 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 (14,15). Initially, those patients
ated with disease (30).
selected for analysis were both dysmorphic and had significant
The criterion for identifying whether or not a gene is patho-
mental retardation. The deletions that have been detected have
logical is by identifying coding sequence abnormalities that
been large and generally incorporating several genes.
are not found in appropriate control populations. For microde-
letions associated with dysmorphic feature and mental retar-
dation, 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- ciency of a single gene. For some microdeletion syndromes
nology leading to more extensive coverage of the genome, e.g. 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. Initially, the development has been on the X causes which of the phenotypic features. For the recently
chromosome, as this chromosome is well annotated and a described 9q34 deletion syndrome, 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). Further developments to generate a gantly identified by collecting a series of patients with smaller
R112 Human Molecular Genetics, 2006, Vol. 15, Review Issue No. 2
and smaller deletions and identifying an apparently balanced
translocation with the phenotype (31). Demonstrating the dis-
ruption of a gene at a balanced translocation breakpoint is still
insufficient to be confident that a particular gene causes
disease as subtle gain or loss of genetic material in individuals
with translocations and no phenotype have been described
(32). The final identification of a point mutation in a single
gene within 9q34 in euchromatic histone methyl transferase
1 (EHMT1) has assigned this phenotype to a specific disease-
causing gene (33). This gene now adds to the list of diseased
genes where mental retardation is the predominant feature
with or without additional clinical or dysmorphic features.
CODING ABNORMALITIES IN SINGLE GENES
The identification of genes that cause disease have usually
relied on the characterization of familial cases. Where the
mental retardation is severe in the family, it is usually effec-
tively a reproductive lethal mutation and therefore autosomal
dominant pedigrees are unlikely to appear in the population.
The prevalence of diseased genes is therefore dependent of
the new mutation rate, for autosomal dominant forms. Where
the phenotype is common i.e. mental retardation without syn-
dromic features, the identification of these individuals is clini-
cally difficult and thus the number of characterized autosomal
dominant genes that give rise to mental retardation is low.
The identification of novel genes has relied on the collecting
of individuals with mental retardation and distinct dysmorphic
features in order to analyse and group together. Conditions like
Smith-Magenis syndrome and Rubinstein-Taybi have been
identified this way and the single genes that are sufficient to
cause the phenotype have been identified by systematic deletion
mapping and point mutation analysis (34,35).
For autosomal recessive causes of mental retardation, the use
of homozygosity mapping in highly consanguineous families
with affected siblings has great potential power. Although
there are likely to be a significant number of genes on auto-
somes that cause mental retardation, the identification of
these genes has been relatively slow. Three genes, PRSS12 on
chromosome 4q26, CRBN on chromosome 3p26 and most
recently CC2D1A on chromosome 19p13.12 have been ident-
ified using autozygosity mapping of highly consanguineous
families (36 38). This method is powerful for detecting auto-
somal recessive genes that cause disease but require the identi-
fication of rare families with the condition and the enrichment
of a population by a founder mutation that will have occurred
by chance. The anticipation is that many new genes will
emerge using this technique in the next 5 10 years, but it is
unlikely to reveal all autosomal recessive genes as it cannot
provide a systematic method of surveying the genome.
X-LINKED MENTAL RETARDATION
The majority of single genes that have been identified, which
give rise to mental retardation are on the X chromosome.
There is a male excess of affected individuals compared
with females (ratio1: 1.3) which has been assumed to be
due to X-linked inheritance both due to the retention of
X-linked genes in the population by the maintenance of
reproductive fitness in females contributing to the prevalence
in the population and the large number of genes on the X
chromosome that gives rise to the condition (1). The first
gene to be identified was FMR1 that causes fragile X syn-
drome and still remains the commonest single gene abnormal-
ity to be identified (39 42). Since 1990, a series of genes have
been identified either by positional cloning or translocation
breakpoint mapping methodologies. Some are only associated
with mental retardation and are not reported to be associated
with dysmorphic or other neurological symptoms and others
are more syndromic although the distinction between these
are gradually becoming less clear as syndromic and non-
syndromic phenotypes are described for several of the genes
(43,44). Currently, genes that are classified as non-syndromic
mental retardation genes are: IL1RAPL1 (45), TM4SF2 (46),
ZNF41 (47), FTSJ1 (48), DLG3 (49), FACL4 (50), PAK3
(51), ARHGEF6 (52), FMR2 (53,54), GDI (55), ZNF81 (56)
and ZNF674 (57), whereas the genes where syndromic
forms of mental retardation is described are NLGN4 (58),
RPS6KA3 (RSK2) (59), OPHN1 (60,61), ATRX (62),
SLC6A8 (63), ARX (64,65), SYN1 (66), AGTR2 (67),
MECP2 (68 70), PQBP1 (56,71), FGD1 (72,73), SMCX
(74) and SLC16A2 (75 77).
In the past 18 months, the number of newly identified genes
has not increased exponentially despite technological advances
suggesting that either nearly all the genes on the X chromosome
have been found or much more likely that the remaining
number of genes that are to be found and now increasingly dif-
ficult to identify because of their rarity. Support for the later
view is the presence of a large number of published and unpub-
lished families with three or four generations affected with
moderate to severe mental retardation and a clear X-linked
inheritance patterns that have not had the causative mutation
identified despite extensive screening of the known genes
suggesting that yet more genes need identification. A systema-
tic but limited search of brain expressed genes within Xp11
region that included 50 genes in this region revealed only
three new genes, and a detailed screen of 70 candidate genes
based on sequence homology and functional similarity to
those that have already been identified in a panel of 300
X-linked families only identified one novel gene where three
missense variants were identified (Raymond et al., unpub-
lished) (78). In order to identify the remaining genes on the
X chromosome that cause mental retardation, a novel systema-
tic approach is needed. The Genetics of Learning Disability
(GOLD) study was established by the authors in Cambridge,
UK, to identify novel genes that cause X-linked mental retar-
dation. The group is using high throughput genomic DNA
sequencing of all coding exons of all genes on the X chromo-
some in a cohort of 200 X-linked mental retardation families
(49). The current estimate of genes to be screened is 854
(http://vega.sanger.ac.uk), and the number of primer pairs
required for coverage is 7200. The criteria for selecting the
family for sequencing is the presence of at least two affected
male individuals, a normal karyotype and no known diagnosis.
Families with the largest pedigrees are prioritized as disease in
these is most likely to be due to a single gene defect. Although
this major project has not reported its completed findings yet, it
is emerging that there are large numbers of unique rare variants
being identified on the X chromosome in the cohort of 200
 Human Molecular Genetics, 2006, Vol. 15, Review Issue No. 2 R113

Figure 1. Mutation analysis of families with X-linked mental retardation. Probands are indicated by black arrows and individuals where mutation tracking was
inconsistent are indicated by red arrows. For the family with a mutation in GPR119 individuals I1, I2, II1, II2, II4, II5, III1 and III2 were tested. For the family
with a mutation in TEX13B individuals II1, II3, III2, III3, III4, III6, IV1 and IV2 were tested. For the family with a mutation in ATXN3L individuals I2, II1, II3,
II4, III1 and III2 were tested. Sequence traces of genomic DNA from the probands are shown with the mutation indicated. The location of the mutations and the
subsequent protein alterations are based on the following RefSeq sequences: GPR119 NM_178471, NP_848566; TEX13B NM_031273, NP_112563; ATXN3L
XN_045705, XP_045705.

families and not all of them are likely to be disease-causing. We
have evidence that truncating mutations are not infrequently
polymorphic and not necessarily associated with the disease
phenotype (Fig. 1). This has important implications for the
molecular genetics community and emphasizes the need to
have samples from distant relatives to track mutations and to
be aware that de novo sequence variants are not necessarily
pathogenic if the phenotype under scrutiny is caused by a
large number of different possible genes. Nevertheless, the
identification of many further genes that cause X-linked
mental retardation hopes to be a significant contribution to
the field.
In addition to the difficulty of finding mutations in large
X-linked families, the observations of Mandel and Chelly
that the prevalence of mutations in ARX in X-linked pedigrees
was high at 6.6% but was only 0.13% in singletons, challenges
the assumption that all male mental retardation is due to high
penetrant abnormalities on the X chromosome (79). This
suggests that in males there is a general predisposition to
mental retardation akin to that of autism where genetic predis-
posing alleles need to be identified and are not necessarily
located on the X chromosome, but may account for the
increased prevalence of disease in male sib pairs quite separate
from the rarer X-linked family pedigrees. This polygenic model
R114 Human Molecular Genetics, 2006, Vol. 15, Review Issue No. 2
of disease would fit with the empirical recurrence risks given,
which are largely based on multiple observations of sib-pair
recurrence risks between 1971 and 1987 and are 2 14% or
8.4% in a most recent population-based study in Atlanta,
USA, where recurrences in children born between 1981 and
1991 for isolated mental retardation were noted (80).
TYPES OF GENES THAT CAUSE MENTAL
RETARDATION
It is emerging that mental retardation can result from a wide
range of protein abnormalities. The genes identified earliest
were frequently signalling molecules in the RhoGTPase
pathway (GDI, PAK3, ARHGEF6) or associated with chromatin
remodelling (RPS6KA3, ATRX). Most recently, components of
the synaptic vesicle or components necessary for its formation,
have been identified as defective (SYN1, SLC6A8, NLGN4 and
DLG3) and a number of novel transcription factors (ZNF41, 81
and 674) have been found. The former is especially exciting as
the identification of mutations in these genes brings together
the earlier work on rodent models of learning and memory
defects which identified molecules in the post-synaptic density
as key mediators of long-term potentiation and depression
(LDP and LTP) (81).
The number of genes identified that cause mental retar-
dation suggests that a mental retardation phenotype can
emerge as the final common pathway of many different
types of abnormal cellular processing and that no one overrid-
ing mechanism is likely to be the cause of mental retardation.
This is both encouraging to us as humans who like to think
that our intellectual processing is both sophisticated and
complex but is somewhat daunting to the mental retardation
biologist who in the early days naively thought that the identi-
fication of the genes responsible for the disease would give us
immediate insights into the mechanism of the disease processes.
Despite the complexity and number of genes that have been
identified, two recent papers have suggested that some defects
of learning and memory may be amenable to therapeutic
agents. McBride et al. (82) demonstrate that synaptic plasticity
and courtship behaviour can be restored in a Drosophila model
of Fragile X syndrome by treatment with metabotropic gluta-
mate receptors (mGluR) antagonists or lithium. Also, the
learning and attention deficits in a mouse model of neurofibro-
matosis type 1 can be restored using an HMG-CoA reductase
inhibitor lavastatin (83). Although these observations are a far
way from suggesting therapeutic effects in humans, the possi-
bility of offering drug treatments for some aspects of learning
disability are now a realistic possibility in the future. The orig-
inal aim to understand the molecular basis of intellectual dis-
ability and to provide an ever improved clinical service to this
group of patients and their families is therefore rapidly being
achieved and exciting new developments are likely to arise in
this field in the next 5 10 years.
THE FUTURE
In the short term, we are likely to identify many more genes
that cause mental retardation. This will begin to define the
numbers of players and pathways that give rise to disease.
The next challenge is to provide cheap, accurate and effective
sequence variant analysis in families with mental retardation.
Together with this we need to develop rapid and effective
functional assessments of pathogenicity of variants for all
genes. Currently, we are only able to offer this for SLC16A2
where free T3 levels are abnormality high and for SLC6A8
where urine and plasma creatine:creatinine levels are
abnormal.
We next need to create and properly assess the validity of
animal models of disease in order to understand the pathways
involved and increase the possibility of therapeutic targets for
learning and memory disabilities in patients in the future.
ACKNOWLEDGEMENTS
This work was funded by the Wellcome Trust, UK. We wish
to acknowledge the help and support from the families in our
study, clinicians and key collaborators Gillian Turner, Jozef
Gecz, Charles Schwartz, Roger Stevenson and the many
members of the Sanger Institute Cancer Genome team lead
by Mike Stratton, Andy Futreal and Richard Wooster.
Conflict of Interest statement. None declared.
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