Genetics of mental retardation
Genetics of mental retardation
AS Ahuja, Anita Thapar, MJ Owen
Department of Psychological Medicine, Cardiff University, Heath Park, Cardiff, United Kingdom
A S Ahuja
Department of Psychological Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN
Indian J Med Sci 2005;59:407-17. [Open Access Article]
Mental retardation can follow any of the biological, environmental and psychological events that are capable of producing deficits in cognitive functions. Recent advances in molecular genetic techniques have enabled us to understand more about the molecular basis of several genetic syndromes associated with mental retardation. In contrast, where there is no discrete cause, the interplay of genetic and environmental influences remains poorly understood. This article presents a critical review of literature on genetics of mental retardation.
Keywords: chromosomal abnormalities; genetic; mental retardation; X-linked
Mental retardation is characterized by significantly below average intellectual functioning existing concurrently with related impaired limitations in two or more of the following applicable adaptive skills areas: communication, self-care, home living, social skills, community use, self-direction, health and safety, functional academics, leisure and work, manifest before the age of 18. The term mental retardation is not in itself a diagnosis, as it does not inform about aetiology, prognosis, or specific treatments. Rather, it refers to a clinical state that is developmental in origin and which affects intellectual and social functioning.
Early literature made a distinction between 'pathological' severe mental retardation (SMR) and 'familial' (usually mild) mental retardation. More recently it has been customary to divide it into two groups according to IQ. Those who show IQ scores between 50 and 70 are categorized as having mild mental retardation (MMR) and those with IQ scores of below 50 are considered as having moderate-severe mental retardation (SMR).'
The impact of molecular genetics on our understanding of disease processes has been enormous and is likely to increase even further. The resurgence of interest in phenotypes combined with the new genetic techniques has reduced the proportion of those with moderate/severe mental retardation in whom the cause is unknown to 20%. Genetic causes may be hereditary or nonhereditary and may not produce specific syndromes. Over 500 recognized syndromes involving a genetic disorder have now been isolated and many have behavioural epiphenomena. A specific cause for mental retardation can be identified in approximately 80% of people with SMR (IQ<50) and 50% of people with MMR (IQ 50-70).
In this article, we will begin by considering what is known about the genetics of idiopathic mental retardation and then move onto discuss specific genetic causes of mental retardation.
Electronic searching was done and the relevant studies were identified by searching Medline, ClinPSYC, CINAHL, EMBASE, PubMed and The Cochrane library using the keywords: mental retardation, genetics, learning disability, chromosomal abnormalities, single-gene defect and X-linked mental retardation. The references cited in the above studies were also searched in order to identify more studies. Also high yield journals related to the topic were identified and were hand searched for relevant articles.
Idiopathic mental retardation
Idiopathic mental retardation refers to individuals who show no
evidence of gross chromosomal defects or single-gene anomalies. It is
sometimes considered as representing the lower end of the IQ
distribution. IQ scores have been shown to have an average weighted
correlation of 0.86 for monozygotic twins and 0.61 for dizygotic twins
and an average correlation between first-degree relatives of 0.4,
suggesting an overall heritability of 50%.
A recent study found twin concordances for mild mental impairment was
74% for monozygotic twins, 45% for same-sex and 36% for opposite sex
dizygotic twins with a group heritability of 0.49.
The aetiology of idiopathic mental retardation is usually explained in
terms of the 'polygenic multifactorial model.' The difficulty is that
there are too few studies to provide sufficiently precise estimates of
the likely role of genes and environment in determining idiopathic
mental retardation. Given the dearth of published literature we are
reliant on attempting to draw conclusions from family and twin studies,
most of which are very old and which report widely varying recurrence
Recent studies of MMR have shown high rates of chromosomal
abnormalities and this raises the possibility that a proportion of
individuals with idiopathic mental retardation may have undetected or
unknown chromosomal aberrations or single-gene defects. Further
advances in molecular genetics may find idiopathic mental retardation
to be an aetiologically heterogeneous group with some individuals
showing retardation secondary to specific genetic causes, others
because of environmental effects and the remainder due to
Single-gene defects account for only a small proportion of mental
retardation and are more likely to be seen in individuals with SMR.
These are well-recognized Mendelian conditions and are characterized by
autosomal recessive, autosomal dominant or X-linked patterns of
inheritance. Many single-gene disorders are syndromic. Syndrome
recognition facilitates diagnosis and has allowed discrete phenotypes
to be delineated. It may be aided by the reference to a dysmorphology
database such as the London Dysmorphology Database-LDDB
(http://dhmhd.mdx.ac.uk LDDB.html). The second database is the Online
Mendelian Inheritance in Man-OMIM (http://www.ncbi.nlm.nih.gov/Omim/).
Another large group of single-gene disorders causing mental retardation
is the in-born errors of metabolism, which have been well documented by
Scriver et al.
In some circumstances, different mutations occurring within the same
gene may cause different clinical phenotypes, depending on how the
mutation affects the production and function of protein involved. This
phenomenon is known as allelic heterogeneity. The majority of inborn
errors of metabolism follow an autosomal recessive pattern of
inheritance, with some notable exceptions, e.g. Hunter syndrome.[Table - 1]
describes some of the common single-gene defect disorders causing mental retardation. X-linked mental retardation
X-linked disorders are due to germline mutations in genes on the
X-chromosome and characteristically affect males. Carrier women usually
have few, if any, manifestations. The large contribution of X-linked
genes to mental retardation is striking and estimated to occur in about
1 in 600 male births. Many X-linked conditions with characteristic
phenotypes are associated with mental retardation [Table - 2]
There are also a considerable number of X-linked nonsyndromic mental
retardation syndromes, where certain clinical phenotypic features are
associated with learning difficulties.
Over 200 heritable X-linked disorders associated with mental
retardation are known and almost a third of these fall into the
category of nonspecific XLMR, with no other features present apart from
The commonest cause of XLMR is the Fragile X syndrome. Manifesting
females have been described in several of the XLMR disorders. In some
conditions, such as Coffin-Lowry syndrome,
females always manifest, whereas in other disorders, carrier females
are usually phenotypically normal but may occasionally manifest
symptoms as a result of altered Lyonization 
or the presence of an X-autosome translocation. In the latter case, the
breakpoint on the X-chromosome affects the function of the XLMR gene
concerned. Some forms of XLMR, which follow an X-linked dominant
pattern of inheritance, affect females exclusively and usually, lead to
lethality in males. Perhaps the best example of such a disorder is Rett
syndrome, a neurodevelopmental disorder that occurs almost exclusively
Fragile X syndrome
Fragile X syndrome is the most common inherited cause of mental
retardation and originally derived its name from the characteristic
nonstaining band or fragile site on the X-chromosome. It affects
approximately 1 in 4425 to 6045 males and causes mental retardation in
1 in 8000 females. This syndrome accounts for half of all the X-linked
mental retardation cases and around 0.6% of the population who show
mental retardation. The mean IQ scores in Fragile X males seems to
decline with increasing age, a phenomenon also described in people with
A curvilinear relationship exists between the length of CGG repeat (the
mutation) and the level of intelligence in Fragile X adults.
normal individuals between 6 and 54 CGG repeats are expected with an
average of 30 repeats. The mutation for Fragile X is a heritable
unstable sequence of trinucleotide CGG repeats ranging from 230 to over
The full mutation, when the repeat sequence reaches a critical length
of about 200 copies, is associated with hypermethylation of the repeat
and adjacent region. This results in the failure of FMR1 transcription
and an absence of the FMR1 gene protein product (FMRP), which is
responsible for the characteristic clinical features of fragile X
'Anticipation' occurs when premutations often expand to full mutations
while transmitted by female carriers and the clinical severity of the
disease increases with each successive generation. A milder form of
mental retardation expressed as FRAXE occurs by FMR-2 mutation.
key clinical characteristics of fragile X syndrome are mental
retardation, large ears and a long face and macro-orchidism. In some
adults, there is a characteristic facial appearance, with a large
forehead with supra orbital fullness, long face, long nose, prominent
jaws, high-arched palate and large ears with a bat-eared appearance.
Eye abnormalities such as pale irises may be a subtle finding in some
Epilepsy is reported in about 25% of the cases.
affected individuals show higher rates of speech and language problems,
attentional difficulties and hyperactivity and autistic-like features
such as gaze avoidance and hand flapping.
The observation of this type of behavioural phenotype in conjunction
with early reports of increased rates of Fragile X in autism led to
interest in the relationship between Fragile X and autism.
Chromosomal abnormalities account for 35-40% of SMR and 10% of MMR.
Chromosomal aneusomies (loss or excess of chromosomal material) cause a
gene dosage difference for a large number of genes and the phenotypic
effect is pleiotropic; therefore, they always cause syndromes of
multiple congenital anomalies and mental retardation.
The commonest autosomal abnormalities are trisomies, particularly
involving chromosomes 13, 18 and 21 and these are all associated with
increased maternal age. The most common aneusomy in live newborns is
trisomy 21 (Down syndrome), which is invariably associated with mental
retardation. Almost all chromosomal aneuploidies, which involve an
alteration in the amount of chromosome material, are associated with
mental retardation. It is not certain whether this is due to dosage
effects of specific genes within the duplicated or deleted segments, or
to a more general effect of aneuploidy per se. It is certainly true
that individuals with chromosomal aneuploidy share some nonspecific
features in common such as poor growth, microcephaly, epicanthic folds
and unusual palmar creases, in addition to features more specific to
the chromosomes involved.
Some chromosome abnormalities occur in
the mosaic form (where some cells show the normal 46 chromosomes and
others have an extra chromosome) and for disorders, which are usually
seen in the full form, mosaicism will confer a milder phenotype.
However, there are some conditions, which are lethal in the full form
and are therefore found only in the mosaic form in surviving
individuals. The common chromosomal abnormalities associated with
mental retardation are summarized in [Table - 3]
It is the most common cause of mental retardation and affects
approximately 1 in 1000 live births. The incidence rises with advancing
maternal age at the time of conception. Approximately 94% of the cases
are caused by trisomy 21, 3.5% by translocation and 2.5% by mosaicism.
The majority of individuals have moderate to SMR and some of those with
a milder phenotype have been shown to have a mosaic karyotype. The
critical region for the Down syndrome phenotype is in the region of
with Down syndrome have characteristic clinical features including
short stature, round skull, brachycephaly, neonatal hypotonia, a flat
occiput, flat facial profile, small simply formed ears, protrusion of
the tongue, high arched palate and typical eye signs (e.g. mongoloid
slope of the palpebral fissures, epicanthic fold, Brushfield spots,
premature cataracts, myopia, nystagmus, strabismus, etc.). Common
abnormalities seen in the limbs include a single-palmar crease (simian
crease), incurved fifth fingers, syndactyly (webbed fingers) and a wide
gap between the first and second toes (sandal gap). Congenital heart
defects (e.g. atrial or ventricular septal defect, mitral valve
prolapse, patent ductus arteriosus) occur in 40% of infants and are a
common cause of death. There is predisposition to Hirschprung's
disease, hypothyroidism and leukaemia and the early onset of
Recent advances in cytogenetic analysis techniques such as high
resolution chromosome banding and fluorescent in situ hybridization
(FISH) together with microsatellite analysis
have enabled the detection of increasingly small chromosomal
abnormalities. The microdeletions are usually small- (4 kb) or less-
and encompass multiple genes, which may all contribute to the
phenotype. Those microdeletions, which are observed most commonly, tend
to have similar breakpoints, occurring in regions of the chromosome
where there is a repetitive DNA sequence. Di George syndrome (velocardiofacial syndrome)
It is the commonest microdeletion syndrome and involves a deletion of
chromosome 22q11. It has an estimated incidence of 1 in 5000. Multiple
anomalies are seen including a cleft palate, velo-pharyngeal
insufficiency (causing feeding difficulties), hypocalcaemia and
Cardiac malformations described are ventricular septal defect,
tetralogy of Fallot, interrupted aortic arch, pulmonary atresia and
Hypotonia is present in half of the patients. Relatively slender hands
with hypotonic and hyperextensible fingers are not uncommon. The facies
are dysmorphic with a broad nasal bridge, narrow alae nasae that are
often notched, small mouth and chin and overfolded helices. The
features vary considerably from person to person, with the speech and
swallowing difficulties being the most consistent features. There is an
excess of psychotic disorders in these individuals. The most recent
study found that more than one quarter fulfilled diagnostic criteria
Although language and motor developmental delay and persistent
co-ordination deficits are common, intelligence is usually in the
The region of chromosome 15q11-13 is subject to the phenomenon
known as genomic imprinting. The genetic information of maternal and
paternal origin is manifested differently in this region. The
individuals who have a microdeletion of 15q11-13 manifest different
characteristics depending on whether the deletion is maternal or
paternal in origin. A paternal deletion gives rise to features of the
and a maternal deletion gives rise to features of Angelman syndrome.
These conditions can also arise from maternal and paternal uniparental
disomy for chromosome 15 leading to Prader-Willi syndrome and Angelman
Prader-Willi syndrome is also known as
HHHO (H, hypotonia; H, hypogonadism; H, hypomentia; O, obesity). It is
a rare condition with a prevalence of 1.2-1.3 per 10 000. It is
characterized by neonatal hypotonia, hyperphagia (over eating),
obesity, hypogonadism, short stature and mild to moderate mental
retardation. Feeding difficulties such as absence of swallowing and
sucking reflexes are common in the initial stages. The hands and feet
are often small and the facies are distinctive, with bitemporal
narrowing and almond-shaped palpebral fissures.
speech, sleep and behaviour are common. A remarkable area of cognitive
strength is their visual-spatial integration as they may show unusual
skill with jigsaw puzzles.
Temper tantrums, self-injurious behaviour particularly in the form of
skin picking and obsessional behaviour are frequently observed.
A deletion in the maternally derived long arm of chromosome 15
(q11-q13) will give rise to the symptoms of Angelman syndrome. It is
also known as the ' Happy puppet syndrome.
It affects between 1 in 20 000 and 1 in 30 000 people and is
characterized by ataxia, jerky limb movements and abnormal gait, absent
speech and SMR. Typical facial features consist of a long face and
prominent jaw, a wide mouth with widely spaced teeth, thin upper lip,
mid facial hypoplasia, deep set blue eyes, blonde hair and
microcephaly. Other characteristic features include epilepsy (about
86%) and/or an abnormal EEG, inappropriate bouts of laughter, tongue
thrusting movement, mouthing behaviour and a happy, social disposition.
Sex chromosome anomalies
Abnormalities in the number of sex chromosomes are generally less
devastating in their effects than aneuploidies in the autosomes. Sex
chromosome anomalies occur in roughly 1 in 400 live births.
These abnormalities cause mild decreases in IQ (5-15 points) in
relation to the family's mean IQ. These anomalies are commonly due to
chromosomal nondisjunction, the risk of which increases with maternal
age. The most common include Turner's syndrome (45,XO), Klinefelter's
syndrome (47XXY) and the 47XXX and 47 XYY karyotypes. All four are
associated with a slight decrease in IQ, as evidenced by comparison
with siblings and by their higher frequency in mentally retarded
Turner's syndrome affects 1 in 2000 to 1 in 5000 females. It is
characterized by the complete or partial absence of one X-chromosome
(45XO). The clinical features include short stature, a webbed neck,
increased carrying angle of the elbow, failure to develop secondary
sexual characteristics and visuo-spatial deficits. Interesting recent
data suggest the X-chromosome might also play an important role for
other sorts of cognitive skills, which facilitate social interaction.
Girls tend to show superior levels of skills such as the ability to
respond to cues in the behaviour of others, to inhibit distractions and
to develop strategies of action compared with boys. Females affected by
Turner's syndrome, whose X-chromosome is of maternal origin show poorer
social cognitive skills than those who possess a paternally derived
Klinefelter's syndrome (47XXY) affects approximately 1 in 1000 males.
In about two-thirds of cases the anomaly is due to maternal
nondisjunction and is nonfamilial.
These individuals have high rates of speech and language disorders
(Ratcliffe 1994). It was originally thought that affected individuals
showed increased rates of mental retardation, psychiatric disorder and
criminality. However early studies of the XXY behavioural phenotype
were based on highly selected samples of those who had been
and it is now recognized that the majority who possess this karyotype
are of normal intelligence and show no increased rates of behavioural
Recent advances in identifying previously undetected
sub-microscopic chromosomal anomalies have proven to be successful.
They highlight the fact that many cases of idiopathic mental
retardation may have specific aetiologies, which may not yet be
discovered. Given the increased interest in studying behavioural
phenotypes associated with some of these conditions, it is hoped that
the localization of specific genes and the identification of genes
within critical chromosomal regions might pave the way for
understanding more about the genetic basis of behaviour and psychiatric
The challenge for the future is to unravel the
complex interaction between genes and environment using well-designed
twin and adoption studies as well as molecular genetic strategies so as
to determine the extent to which genes and environment contribute,
co-act and interact in determining intelligence. Such research will
contribute in planning appropriate interventions.
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