Chapter 2
Knight SJL (ed): Genetics of Mental Retardation.
Monogr Hum Genet. Basel, Karger, 2010, vol 18, pp 16–30
Mental Retardation: Definition, Classification and
Etiology
R. Regana ⭈ L. Willattb
a
University College Dublin, Dublin, Ireland; bAddenbrooke’s Hospital, Cambridge, UK
Abstract
Mental retardation (MR) is a widely used term but a con-
tentious one. There is still a quest for appropriate termi-
nology that does not associate with negative perceptions
of affected individuals and yet is accurate in terms of noso-
logy. Also controversial is the most appropriate method-
ology for measuring the degree of mental retardation in
affected individuals. Despite this, it is agreed that mental
retardation is a common, usually lifelong condition with
a complex multifactorial etiology. Studies on the preva-
lence of MR have given varied estimates particularly for
mild MR due to ascertainment biases and variable defini-
tions. However, moderate to severe MR is estimated at 3.8
per 1,000 and mild MR at ~30 per 1,000. Genetic anoma-
lies are causative in a significant proportion of moderate
to severe MR and scientific understanding of these has
increased substantially in recent decades. In addition to
the definition, classification and etiology of MR, this chap-
ter revisits some classical MR syndromes associated with
chromosomal abnormalities, including Down syndrome,
Cri du Chat syndrome, Wolf-Hirschhorn syndrome and
fragile X syndrome.
Copyright © 2010 S. Karger AG, Basel
Introduction to Nomenclature
‘What’s in a name? that which we call a rose by any
other name would smell as sweet’ [1]. In fact there
seems to be quite a lot in a name when it comes
to mental retardation (MR), a term still used ex-
tensively in scientific and medical literature but
considered to have a negative connotation in the
public arena. The world’s oldest organization
of professionals dealing with the disorder, the
American Association on Mental Retardation,
changed its name in 2007 to the American
Association on Intellectual and Developmental
Disabilities (AAIDD), reflecting the importance
of the name. However, a change in name did not
mean a change in definition: ‘it is crucial that
‘mental retardation’ and ‘intellectual disability’
should be precisely synonymous in definition and
in all related classification because of the legal im-
plications of a term change’ [2].
The descriptive terms that are used in place of
mental retardation include mental handicap, men-
tal disability, intellectual disability, cognitive im-
pairment and depending on the age of the individ-
ual, developmental delay and learning disability.
In the UK, the term learning disability is still the
recommendation, though this is open to misinter-
pretation since in the USA learning disability refers
to problems affecting schoolwork (as opposed to
‘learning difficulties’ in the UK). In Australia, ‘in-
tellectual disability’ is commonly applied whereas
in much of Europe and North America, MR is still
typically used because this is more specific than
terms such as ‘developmental disability’ that also
include other disorders that do not involve MR.
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 The debate on the most appropriate term is on-
going and reflects a general dissatisfaction with
the nosological status and negative perception of
the disorder [3, 4]. Given that there is not yet a
consensus across all continents, we will use the
term MR for the remainder of this chapter.
Definition of MR
In the UK, the most common definition of MR
is provided by the World Health Organization’s
International Classification of Diseases (ICD-
10), whilst in the USA the American Psychiatric
Association Diagnostic and Statistical Manual of
Mental Disorders (DSM-IV-TR) criteria are ap-
plied. These are broadly similar and define MR as
substantial limitations in functioning that mani-
fests before the age of 18. There must be signifi-
cantly sub-average intellectual functioning ac-
companied by limitations in two or more of the
following skills: communication, self care, home
living, social skills, community use, self direc-
tion, health and safety, functional academics, lei-
sure and work [5, 6]. For children younger than 5
years of age the term global developmental delay
is used. It is defined as a significant delay in two
or more domains, including gross or fine motor
development, speech/language, cognition, social/
personal development and activities of daily liv-
ing and it is thought to predict the future mani-
festation of mental retardation [7].
The aim of the MR definition is to emphasize
the amount of support needed for the individual
to succeed in society, rather than to highlight the
degrees of impairment. This approach displays a
correct and humane attitude to the individual and
is of enormous benefit to the planning and pro-
vision of services to help those with disabilities.
However, in terms of epidemiological studies, the
definition offers an assortment of problems. First,
it does not account for those individuals with MR
who die in the prenatal period or during infan-
cy. Second, there is disagreement by what exactly
Definition, Classification and Etiology of MR
is meant by ‘general intellectual functioning’ and
how it is measured. Third, the ten adaptive skills
given are neither empirically selected, nor weight-
ed according to importance. Although there are
standardized tests, no single measure of adaptive
behaviour exists that measures these particular
ten skill domains. Finally, the presence of behav-
ioural difficulties that may affect behavioural and
intellectual assessments means that individuals
with such problems may be over represented [8].
Classification
The classification of mental retardation is largely
based on the measurement of intellectual func-
tioning by Intelligence Quotient (IQ) tests. The
components of these tests, what they are designed
to measure and the interpretation of the results
are areas of considerable debate [9, 10]. The first
attempt to measure mental ability was set out in a
test by Francis Galton at the end of the 19th centu-
ry. The test measured such aspects, amongst oth-
ers, as colour sense, breathing power and force of
blow [11]. These were justified to have an impact
on intelligence on the basis that ‘the more percep-
tive the senses are of difference, the larger is the field
upon which our judgment and intelligence can act’
[12]. Modern IQ tests have progressed substan-
tially since then and set out to measure a num-
ber of diverse abilities such as spatial ability, ver-
bal ability and memory, speed of processing and
non-verbal reasoning through applying a battery
of tests. The result of each test is then added to
create a composite score.
The criticisms of IQ tests are many and range
from the cultural bias of the tests to disagree-
ments on the concept of what they try to measure
[9]. The latter debate centers on whether IQ tests
measure a single fundamental process of gener-
al intelligence, which permeates all intellectual
activities or whether intelligence is better con-
ceived as a set of quite independent faculties or
relatively specialized cognitive processes. There
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is significant positive correlation between the re-
sults of one IQ test and another. This appears to
support the theory of a single functional process
of intelligence. However, proponents of the multi-
ability view attribute this positive correlation to
the overlap between those cognitive processes
measured by different tests (arguments which
are fully explored in the Novartis Foundation
Symposium 223 [13]).
Despite criticism of the existing IQ tests, there
is no other test available that has been validated
as a measure of intelligence that has not positive-
ly correlated with IQ scores, especially in adults.
Furthermore, although theoretically distinct and
measured in different ways, IQ and adaptive be-
haviour are often highly correlated, especial-
ly in people with moderate to profound mental
retardation [14]. Despite their inherent limita-
tions, IQ tests are therefore considered to be the
most practical method for classifying intellectual
ability, both for individual and epidemiological
purposes.
There are a variety of IQ tests available. For
children with learning disability the test employed
depends on the age of the child and their motor
and sensory development. The Bayley Scales of
Infant Development (BSID) [15] is one of the
most common assessments used for the mental,
motor and behaviour development of children
under 42 months. In the mental scale evaluations,
which yield a score called the mental develop-
ment index, it evaluates sensory/perceptual acu-
ities, discriminations and response; acquisition
of object constancy; memory learning and prob-
lem solving; vocalization and beginning of verbal
communication; basis of abstract thinking; habit-
uation; mental mapping; complex language; and
mathematical concept formation. The Wechsler
Intelligence Scale for Children (WISC) [16], de-
veloped by David Wechsler, is an intelligence test
for older children between the ages of 6 and 16
inclusive that can be completed without reading
or writing. Currently in its 4th edition, the test
comprises ten core subtests. These subtests then
18
generate a full scale score (FSIQ,) and four com-
posite scores known as indices: Verbal compre-
hension, perceptual reasoning, processing speed
and working memory.
The WISC is one of a family of Wechsler in-
telligence scales. Individuals over 16 years of age
are tested with the Wechsler Adult Intelligence
Scale (WAIS®-IV), and children ages 3 to 7 years,
3 months are tested with the Wechsler Preschool
and Primary Scale of Intelligence (WPPSI).
However, there is a battery of IQ tests available
and further details are given in Chapter 5, on the
clinical evaluation of patients with MR.
Intelligence follows a normal distribution re-
flecting that it is a multifactorial trait (fig. 1).
In IQ tests the items used are age adjusted and
assembled to give a normal distribution with a
mean of 100, and a standard deviation of ap-
proximately 15 units. IQ scores more than two
standard deviations below the mean, i.e. lower
than 70, are regarded as indicators of mental re-
tardation. The severity of the condition may be
categorized further by IQ scores into borderline
normal (IQ 71–85), mild (50–70), moderate (35–
50), severe (20–35) and profound (<20) MR with
the exact cut-off points varying slightly between
the DSM-IV TR and ICD-10 classifications. The
AAIDD classification system gives more empha-
sis to the intensity of the support required and
here the level of mental retardation is divided
into four groups: intermittent, limited, extensive
and pervasive support, a system that requires a
more comprehensive multidisciplinary assess-
ment of types of support required in individuals
with MR.
Syndromic and non-Syndromic MR
Traditionally, inherited forms of MR for which
there is considered to be a direct causal link be-
tween a genetic anomaly and the MR have been di-
vided into syndromic and non-syndromic forms.
In syndromic MR, the patients have additional
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 34% 34%

68%

14% 14%

2% 2%
0.1% 95% 0.1%

55 70 85 100 115 130 145

Fig. 1. Normal distribution of intelligence. The graph of a normal distribution

is a smooth curve that idealizes real-life data histograms. The mean of the
distribution (μ) is the number that lies directly beneath the peak of the curve.
The standard deviation of the distribution (σ) is the distance from the mean
to numbers directly beneath the inflection points of the curve. In IQ tests the
mean is set at 100 units and standard deviation is 15 units.

physical, behavioural, or neurological symptoms
whereas in non-syndomic MR, the only clinical
feature is the MR. However, the distinction be-
tween the two categories is gradually becoming
blurred because increasing numbers of single
genes are being discovered in which mutations are
associated with both syndromic as well as non-
syndromic forms, for example, ARX, MECP2 and
FMR1 (see also Chapter 8).
Prevalence
Establishing the true prevalence of MR has been
difficult. Generally studies have been designed to
aid the planning of support services. These esti-
mates establish an ‘ascertained’ prevalence rate,
which is the number of cases officially recorded
by the authorities. Ascertainment will usually fa-
vour those of school age over those in infancy,
when developmental problems have not yet come
to light, or those in adulthood, when there may
be less involvement with authorities and less pres-
sure to develop new skills. The ‘true’ prevalence
rate is the overall proportion of mentally retarded
people in a population, whether or not they re-
quire services.
In an attempt to establish valid estimates of
true prevalence rates for severe and mild mental
retardation, Roeleveld and colleagues reviewed
and critically evaluated all published studies
since 1960 [17]. The authors found that the prev-
alence rate of moderate to severe MR in children
of school age is relatively stable in the majority
of studies, with an average value of 3.8 per 1,000.
Furthermore, gender-specific rates were remark-
ably constant and indicated a 20% excess of males
in the group. This consistency of prevalence rates
across different studies was not found for cases of
mild mental handicap. Here, the variation in prev-
alence rates was enormous, ranging from 4 per
1,000 to 79 per 1,000. This disparity reflects the
low number of studies specific to this group and
the immense problems in equating methodology.
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Definition, Classification and Etiology of MR 19

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In the absence of formal assessment distinguish-
ing low IQ from poor concentration and attention
abilities, reporting of accurate prevalence rates is
confused. Reports of ‘learning disability or diffi-
culty’ may in fact be attention deficit hyperactivity
disorder (ADHD) or even autistic spectrum dis-
order (ASD). It should be noted that the extremes
in prevalence rates were found in those popula-
tions with greatest differences in their social and
economic environments which probably reflects
the complex social and educational factors that
contribute to mild MR. By excluding problems
with methodology and the ascertained prevalence
rates, a tentative true average prevalence for mild
MR in children of school age was calculated to
be 30 per 1,000 [17]. This figure is in accordance
with the figure proposed by more recent preva-
lence reports as reviewed by Leonard and Wen (33
per 1,000) [18] and with WHO [5].
Etiology
As outlined in Chapter 5, establishing a diagnosis
for MR in an individual has a number of impor-
tant benefits. However, despite advances in medi-
cal knowledge and the diagnostic tests available,
the cause of the MR in a significant proportion
of individuals remains unknown. Table 1 shows
the relative frequencies of different etiologies of
MR, including non-genetic causes. Estimates of
the diagnostic yield (10–81%) in children with
mental retardation are highly variable [19, 20].
This apparent variability can be attributed to dif-
ferences in a number of factors including sample
population characteristics, severity of delay in the
children studied, the extent of previous diagnos-
tic investigations and technological advances over
time, especially with respect to genetic and neuro-
imaging techniques. In addition, some studies in-
clude conditions such as cerebral palsy as a medi-
cal diagnosis.
The majority of surveys of the etiology of
individuals with mental handicap have been
20
Table 1. Causes of mental retardation (MR) [19]
Cause of MR %
Chromosomal 4–28
Recognizable syndromes 3–7
Known monogenic syndromes 3–9
Structural (central nervous system) 7–17
Complications of prematurity 2–10
Environmental/teratogenic causes 5–13
Cultural familial MR 3–12
Provisionally unique, monogenic syndromes 1–5
Metabolic/endocrine 1–5
Fetal alcohol syndrome 0.5–1
Unknown 30–50
of populations in industrialized countries and
many of the early studies were carried out on
institutionalized patients. The exception to this
is a study carried out on the total population of
North East region of Scotland, UK [21]. For rea-
sons outlined earlier, complete ascertainment is
often difficult: as early studies were largely in-
stitution-based, they tended to produce system-
atic biases in the relative frequency of different
conditions, such as those with associated severe
physical and/or psychiatric disorders. Other
sampling problems include different methods
of disease classification in different surveys, the
uncertainty of attributing abnormalities to pla-
cental insufficiency and/or minor birth asphyxia
and the recognition of new syndromes.
Environmental factors are thought to account
for approximately 20% of cases of moderate to se-
vere MR and 10% of mild MR: they usually oc-
cur prenatally or during early infancy causing
brain injury. Among the environmental factors
are infectious diseases (such as cytomegalovirus
infection during pregnancy and postnatal men-
ingitis), very premature birth, perinatal anoxia,
hypothyroidism, maternal malnutrition and fetal
alcohol exposure [19]. Metabolic disorders such
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as phenylketonuria, hypothyroidism and galac-
tosemia are frequently detected by targeted new-
born screening and may also have been overrep-
resented in earlier etiological studies.
What is clear from table 1 is that, where a diag-
nosis has been reached, there is an overwhelming
contribution by genetic factors in the etiology of
MR [19, 22], Chromosomal abnormalities have a
particularly significant role and in the next sec-
tions we review some classic chromosomal abnor-
malities and syndromes associated with MR.
Chromosomal Abnormalities Associated with
MR
An integral part of the diagnostic investigation
of individuals with MR is chromosome analysis.
Here, a cytogeneticist uses a microscope to exam-
ine chromosome integrity. Initially, only the num-
bers and shapes/sizes of the chromosomes could
be categorized, but later banding techniques were
developed that enabled each individual chromo-
some to be identified and its integrity assessed.
This approach, known as karyotyping, is a genome
wide test, with a resolution of 5 to 10 megabas-
es (Mb) of DNA. The human genome contains
over 3,000 Mb of DNA and 20,000–25,000 genes,
and therefore the changes identified usually en-
compass many genes. Several chromosomal ab-
normalities associated with specific syndromic
forms of MR have been identified by chromo-
some analysis. These include aneuploidy (loss or
gain of a complete chromosome) and segmen-
tal aneuploidy (loss or gain of part of a chromo-
some), which are both relatively common events,
though not all will result in a viable fetus. In addi-
tion, apparently balanced causative chromosomal
rearrangements such as translocations and inver-
sions as well as phenomena such as the fragile site
FRAXA, which is induced under specific cell cul-
ture conditions, may be identified. A list of well-
known rearrangements that are associated with
MR is given in table 2.
Definition, Classification and Etiology of MR
Aneuploidy
Aneuploidy is common at conception. It has
been estimated that at least 25% of blastocysts are
chromosomally abnormal [23, 24]. Monosomic
conceptions are lost earlier in pregnancy than
trisomies and the chromosomal abnormalities
observed in clinically recognizable pregnancy loss
reflect the viability of the chromosome abnormal-
ity. The chromosomally abnormal aneuploidies
that can survive to term and are associated with
MR are trisomy 21, trisomy 18 and trisomy 13
(Down, Edwards and Patau syndromes, respec-
tively), chromosomes that contain the least genet-
ically significant material. Down syndrome (DS)
is the most common genetic cause of MR; the
other aneuploidies are individually rare but com-
bine to make up a significant proportion (table 1).
Both Patau and Edwards syndromes are charac-
terized by severe MR, intrauterine growth restric-
tion, microcephaly, congenital heart defects and
several other anomalies of variable degree. Of the
live borns with Patau and Edwards syndromes,
90–95% do not survive to 1 year of age.
Trisomy 21: Down Syndrome (OMIM 190685)
Trisomy 21 is the most common diagnosable
cause of MR and occurs in 1 out of 700 live births
[25]. The clinical phenotype associated with tri-
somy 21 was first described by J. Langdon Down
in 1866 [26]. In addition to the characteristic fa-
cial appearance, body build and mental impair-
ment, nearly 80 different clinical signs have been
identified in individuals with DS including con-
genital heart disease, duodenal stenosis or atre-
sia, imperforate anus, Hirschsprung disease,
muscle hypotonia, immune system deficiencies,
increased risk of childhood leukaemia and early
onset Alzheimer’s disease [27]. However, DS indi-
viduals have a lower risk for solid tumours. In ec-
onomically developed countries individuals with
DS may live to their 70s but overall the survival
rate is significantly less than the population aver-
age, a 1997 study estimating it at 49 years [28].
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Table 2. Well-known syndromes and chromosomal rearrangements associated with MR

Syndrome Chromosomal OMIM Key clinical features

aberration

Down trisomy 21 #190685 Characteristic face, congenital malformations

particularly of the heart (30–40%) and
gastrointestinal tract. Significant hearing loss
(90%).

Edwards trisomy 18 In utero, the most common characteristic is

cardiac anomalies, followed by central nervous
system anomalies such as head shape
abnormalities. In birth, growth deficiency,
feeding difficulties, breathing difficulties and
arthrogryposis.
Low-set, malformed ears, micrognathia, cleft lip/
cleft palate, upturned nose, palpebral fissures, a
short breast bone, clenched hands,
underdeveloped thumbs and/or nails, absent
radius, webbing of the second and third toes,
clubfoot or Rocker bottom feet and undescended
testicles in males.

Patau trisomy 13 Holoprosencephaly, polydactyly, cardiac lesions.

Cat eye +idic(22) #115470 Coloboma of the iris and anal atresia with fistula,
downslanting palpebral fissures, preauricular
tags and/or pits, frequent occurrence of heart
and renal malformations; growth retardation is a
variable feature as is mental retardation. The
majority of patients function in the borderline
normal to mildly retarded range, a few are
normal, and some are moderately to severely
retarded, although the latter condition is rare.

Pallister Killian +idic (12) #601803 Profound mental retardation, seizures, streaks of
hypo- or hyper-pigmentation, and facial
anomalies, including prominent forehead with
sparse anterior scalp hair, flat occiput,
hypertelorism, short nose with anteverted
nostrils, flat nasal bridge and short neck.

Fragile X FRAXA site #300624 Moderate to severe mental retardation,

expression macroorchidism, high arched palate,
(CGG repeat hyperextensible joints and distinct facial features,
expansion) including long face, large ears and prominent
jaw.

Wolf Hirschhorn del(4p) #194190 Severe growth retardation and mental defect,
microcephaly, ‘Greek helmet‘ facies, and closure
defects (cleft lip or palate, coloboma of the eye
and cardiac septal defects).
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Table 2. Continued

Syndrome Chromosomal OMIM Key clinical features

aberration

Cri du Chat del(5p) #123450 Incidence 1 in 20,000 to 1 in 50,000 (IQ <20,

incidence 1%). Microcephaly, round face,
hypertelorism, micrognathia, epicanthal folds,
low-set ears, hypotonia and severe psychomotor
and mental retardation.

Chromosome 18p del(18p) #146390 Mental retardation, growth retardation,

deletion craniofacial dysmorphism including round face,
dysplastic ears, wide mouth and dental
anomalies, and abnormalities of the limbs,
genitalia, brain, eyes, and heart. Round face
characteristic in the neonatal period and
childhood may change to a long face with linear
growth of the height of the face.

Chromosome 18q del(18q) #601808 Mental retardation, short stature, hypotonia,

deletion hearing impairment and foot deformities.

Prader-Willi del(15)(q12) #176270 Diminished fetal activity, obesity, muscular

hypotonia, mental retardation, short stature,
hypogonadotropic hypogonadism and small
hands and feet.

Angelman del(15)(q12) #105830 Absence of a maternal contribution to the

imprinted region on chromosome 15q11-q13.
Mental retardation, movement or balance
disorder, characteristic abnormal behaviors and
severe limitations in speech and language.

Williams-Beuren del(7)(q11.23) #194050 Supravalvular aortic stenosis (SVAS), multiple

peripheral pulmonary arterial stenoses, elfin face,
mental and statural deficiency, characteristic
dental malformation and infantile hypercalcemia.

22q11.2 deletion del(22)(q11.2) #188400 Neonatal hypocalcemia from parathyroid

DiGeorge/VCFS hypoplasia, thymic hypoplasia and outflow tract
defects of the heart. Short stature and variable
mild to moderate learning difficulties are
common.

Smith-Magenis del(17)(p11.2) #182290 Brachycephaly, midface hypoplasia, prognathism,

hoarse voice, speech delay with or without
hearing loss, psychomotor and growth
retardation and behavioral problems.

Miller-Dieker del(17)(p13.3) #247200 Lissencephaly, microcephaly, small mandible,

lissencephaly bizarre facies, failure to thrive, retarded motor
development, dysphagia, decorticate and
decerebrate postures.
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Definition, Classification and Etiology of MR 23

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Table 2. Continued

Syndrome Chromosomal OMIM Key clinical features

aberration

Langer-Giedion del(8)(q24) #150230 Sparse scalp hair, winged scapulae, multiple

cartilaginous exostoses, redundant skin. Bulbous
nose with tented alae, large laterally protruding
ears, elongated upper lip and mental retardation.

Potocki-Shaffer del(11)(p11.2) #601224 Foramina parietalia permagna, multiple

exostoses, craniofacial dysostosis and mental
retardation.

Beckwith-Wiedemann dup(11)(p15) #130650 Exomphalos, macroglossia and gigantism in the

neonate. Paternally derived duplications,
increased incidence of moderate to severe MR.

Jacobsen del(11)(q23) #147791 Growth retardation, psychomotor retardation,

trigonocephaly, divergent intermittent
strabismus, epicanthus, telecanthus, broad nasal
bridge, short nose with anteverted nostrils, carp-
shaped upper lip, retrognathia, low-set
dysmorphic ears, bilateral camptodactyly,
hammertoes, and isoimmune thrombocytopenia.

Sotos del(5)(q35) #117550 Excessively rapid growth, acromegalic features,

and a non-progressive cerebral disorder with
mental retardation. High-arched palate and
prominent jaw.

1p36 deletion del(1)(p16) #607872 Developmental delay and mental retardation.

Deep set eyes, flat nasal bridge, asymmetric ears
and pointed chin. Seizures, cardiomyopathy and
hearing impairment.

22q13.3 deletion del(22)(q13.3) #606232 Neonatal hypotonia, global developmental delay,

normal to accelerated growth, absent to severely
delayed speech, autistic behavior, minor
dysmorphic features.

ATR-16 del(16)(p13.3) #141750 Haemoglobin H disease (microcytic hypochromic

anemia and normal iron status) with multiple
congenital anomalies: spina bifida from T6 to the
sacrum with a T10-L4 myelomeningocele,
congenital cataracts, bilateral inguinal hernias,
bilateral deformities of the femoral necks and
subluxation of the left hip.

The vast majority of meiotic errors leading to
trisomy 21 occur in the egg, as nearly 90% of cases
involve an additional maternal chromosome [29].
The risk of having a pregnancy with trisomy 21 is
higher in older women; mothers below 25 years
of age have an average risk of about 1:1,400 rising
to about 1:350 at 35 and 1:40 at age 43. The rea-
son for the maternal age effect remains unknown,
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although most studies imply an age-related deg-
radation of the meiotic machinery [29, 30]. More
recently ovarian mosaicism has been suggested as
the major causative factor [31].
Postnatally, the cytogenetic confirmation of a
clinical diagnosis of Down syndrome is impor-
tant for providing accurate genetic advice to the
family. The majority of individuals with Down
syndrome have trisomy 21 in all cells examined.
Parental chromosome analysis is not necessary in
these cases and the parental recurrence risk is not
increased above the maternal age related baseline
risk [32]. In 3% of individuals, there is an unbal-
anced translocation involving chromosome 21.
Many of these are inherited from a parent with a
balanced rearrangement and here the recurrence
risk is high. Complex chromosomal rearrange-
ments involving chromosome 21 and producing
a Down syndrome phenotype are rare (0.5%).
Mosaicism for trisomy 21 is present in around 1%
of Down syndrome individuals and this may re-
sult in a milder condition. It has been suggested
recently that trisomy 21 mosaicism is more com-
mon than previously recognized, and therefore
screening for mosaicism is advisable [33].
Establishing which genes are responsible for
the characteristic abnormalities of the disease
and the specific cellular and physiological impli-
cations of over-expression of these gene products
in DS has been difficult to elucidate. An almost
complete DNA sequence of the long arm of chro-
mosome 21 has been available for a number of
years and a number of mouse models have been
studied (reviewed in [34]). It is thought that the
transcription factor gene ETS2 and the Copper-
zinc superoxide dismutase (SOD) gene may be
implicated in the lower risk for solid tumors [35].
For MR, it has been hypothesized that the mild to
moderate mental retardation occurs as a result of
over-expression of dual-specificity tyrosine-(Y)-
phosphorylation-regulated kinase 1A (DYRK1A),
synaptojanin 1 (SYNJ1) and single-minded homo-
logue 2 (SIM2). Trisomy for these genes is linked
to learning and memory defects. In particular,
Definition, Classification and Etiology of MR
DYRK1A has shown to play a major role in both
cell cycle regulation and synaptic plasticity and in
mouse models modulation of the DYRK1A gene
copy number can correct brain morphogenesis al-
terations [36].
Segmental Aneuploidy in MR
Segmental aneuploidy is also a relatively com-
mon event and is more likely to result in survival
to term than complete aneuploidy. Interestingly,
some MR syndromes that are now known to be
due to chromosomal deletions had sufficiently
apparent clinical features for a syndromic diag-
nosis to be made even before the implementation
of chromosome banding, e.g. Wolf-Hirschhorn
syndrome (WHS) and Cri du Chat syndrome.
However, the advent of chromosome banding
brought the identification of additional segmen-
tal aneusomy syndromes associated with MR.
Wolf-Hirschhorn Syndrome (OMIM 194190)
In 1961, Hirschhorn published a single case report
documenting the deletion of a B group chromo-
some in a newborn. A second baby with a similar
deletion was identified by Wolf in 1965. The con-
dition associated with this deletion, involving the
terminal portion of the short arm of chromosome
4, became known as Wolf-Hirschhorn syndrome
(WHS). WHS presents with a distinctive clinical
phenotype. The upper facial features of hyperte-
lorism, prominent glabella and broad nasal bridge
led to the descriptive term Greek warrior helmet.
Other features including microcephaly, midline
defects such as cleft palate and hypospadias, con-
genital heart malformations, congenital hypoto-
nia, renal and skeletal anomalies, growth delay
and seizures are all observed in more than 50% of
cases with the classic phenotype. MR is severe in
75% and mild/moderate in 25% of cases and the
mean IQ of affected individuals is 44 [37].
Early studies investigating karyotype/phe-
notype correlations in WHS were hampered by
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the fact that in a significant proportion of cases
(around 20%) the deleted chromosome 4 is the
unbalanced product of a translocation. These are
often de novo translocations and frequently in-
volve the olfactory receptor genes in 8p23 [38].
Prior to the availability of fluorescence in situ hy-
bridization (FISH) and microarray studies (see
Chapter 3) it was assumed that these were small
de novo deletions when in reality they involved a
relatively large deletion of 4p and additionally du-
plication of material from another chromosome,
thus confusing the clinical picture. The classi-
cal WHS phenotype is associated with large de-
letions, averaging between 5 and 18 Mb in size.
These are usually detected by standard chromo-
some analysis, particularly if attention is focused
on chromosome 4. The mild form, usually lacking
major clinical malformations, is associated with
a small deletion not exceeding 3.5 Mb and is un-
likely to be detected without FISH or microarray
studies. The third clinical category results from a
very large deletion exceeding 22–25 Mb causing a
more severe phenotype than typical WHS.
WHS appears to be a contiguous gene dele-
tion syndrome with multigenic pathogenesis.
Two regions within band p16.3 of chromosome
4 have been described as critical regions for the
phenotype: WHSCR1 and WHSCR2. Of these,
WHSCR2, a 300–600-kb interval between loci
D4S3327 and D4S98-D4S168, is the true criti-
cal region. WHSCR2 contains the genes WHSC1
and LETM1 (leucine zipper/EF-hand-containing
transmembrane). Haploinsufficiency for WHSC1
is proposed to result in the characteristic facial
features whereas LETM1, involved in Ca2+ sig-
nalling, is a candidate gene for the seizures ob-
served in 80% of WHS cases. However, to date no
mutations have been found for either gene.
Cri du Chat Syndrome (OMIM 123450)
Cri du Chat syndrome is so named because new-
borns with the condition have a high-pitched cat-
like cry attributable to structural abnormalities
of the larynx (e.g. laryngeal hypoplasia) and/or
26
central nervous system dysfunction. This pass-
es after a few weeks, reinforcing the need for a
good clinical history. Other key features include
microcephaly, broad nasal bridge, epicanthal
folds, micrognathia, abnormal dermatoglyphics,
and severe psychomotor and mental retardation.
Weight, height and head circumference all show
substantial downward shift with age from birth to
18 years. The phenotype in adults is very differ-
ent to children and includes premature greying of
hair. Usually individuals have delayed speech and
language development; some never develop spo-
ken language. Receptive language is better than
expressive language, although both are delayed.
Most cases are de novo, either a deletion or an
unbalanced translocation. However the possibil-
ity of familial translocation should always be con-
sidered. The estimated incidence is between 1 in
15,000 and 1 in 50,000 births [39].
Similar to WHS, Cri du Chat syndrome was
identified before chromosome banding was avail-
able. Lejeune in 1963 [40] found a deletion of a B
group chromosome in newborns with a very dif-
ferent phenotype to WHS and concluded that it
involved chromosome 5. The phenotype arises
from haploinsufficiency of multiple genes, the de-
letion breakpoints ranging from 5p13 to 5p15.2, a
region containing many repetitive sequences like-
ly to account for the instability. Molecular analy-
ses have shown that the deleted chromosome is
mostly paternal [41].
Studying large numbers of cases has revealed
that deletions involving only the terminal short
arm are associated with mild to moderate MR
and speech delay whereas the genes producing
the cat-like cry and typical facial features are lo-
cated within 5p15.2 to 5p15.12. Two genes in this
region, Semaphorin F (SEMAF) and δ-catenin
(CTNND2), may be linked with cerebral develop-
ment and thereby MR. Families with deletion of
the interstitial region, 5p14.3 to 5p14.1, have an ap-
parently normal phenotype. More centromeric de-
letions extending into the p13 band are associated
with more severe, usually profound MR [39, 42].
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Chromosome 18p Deletion Syndrome (OMIM
146390)
Deletion of part or the entire short arm of chro-
mosome 18 was described first in 1963. It has a fre-
quency of 1 in 50,000 live births and is associated
with mild to moderate learning disability (IQ 25
to 75). The main clinical features are short stature,
round face with short philtrum, palpebral ptosis
and large ears with detached pinnae. In 10–15%
of cases, severe brain and facial malformations are
observed; most of these die in early infancy. In
other cases, life expectancy does not appear to be
reduced [43]. Investigating individuals with dif-
ferently sized deletions has helped to refine spe-
cific regions of the chromosome contributing to
the clinical phenotype. A critical region between
bands p11.21 and p11.1 is thought to be linked
with the MR as patients with deletions distal to
p11.21 have borderline or normal mental devel-
opment [44]. Deletions that include the more cen-
tromeric region p11.3 have been associated with
the severe brain and facial malformations. A can-
didate gene for the holoprosencephaly, TGIF, is
located in this region, but only 10–15% of individ-
uals with a TGIF deletion have holoprosencephaly
(HPE). This is a much lower concordance than
observed with other HPE loci [45] and indicates
that TGIF is not fully dosage sensitive or that ge-
netic modifiers are involved.
In about two thirds of cases, the deletion is de
novo and the parental recurrence risk is very small
[46]. Most of the remaining cases are unbalanced
translocations, either de novo or inherited from a
parent with a balanced form of the translocation.
There have been at least six reports of parent-to-
child transmission usually involving the more dis-
tal region of 18p and in these cases there is a 50%
chance of recurrence [47].
Chromosome 18q Deletion Syndrome (OMIM
601808)
Deletions of 18q are one of the most common
segmental aneuploidies compatible with life with
an estimated birth frequency of ~1 in 40,000 live
Definition, Classification and Etiology of MR
births. As familial cases have been described, fer-
tility does not appear to be an issue. The deletions
vary in size with breakpoints ranging from band
q21 to small terminal deletions involving band q23
only [48]. Although the phenotype for a give re-
gion of deletion has been considered to be highly
variable, some of this variability has now been ex-
plained by re-examination of previously reported
cases using FISH or microarrays. Some deletions
thought to be pure terminal deletions have proven
to be interstitial whereas others are interchromo-
somal rearrangements with monosomy for part
of 18q and trisomy for a different chromosome
[49]. A number of features of the 18q deletion
syndrome have now been attributed to particular
regions of deletion. With advanced technology it
has become clear that small deletions of 18q may
be missed by routine chromosome banding anal-
ysis. The increased use of diagnostic Magnetic
Resonance Imaging (MRI) scanning and the use
of microarrays may result in this becoming a more
frequently diagnosed condition.
The FRAXA Fragile Site and Fragile X
Syndrome (OMIM 300624, see also Chapter 8)
Fragile X syndrome (FXS) is the most common
inherited, single cause of mental retardation with
approximately 1 in 4,000 males affected [50]. The
average IQ in affected males is 40, with a range ex-
tending to 70 [51]. Aside from intellectual disability,
prominent characteristics of the syndrome include
an elongated face, large or protruding ears, flat feet,
larger testicles in men (macroorchidism), and low
muscle tone. Behavioural characteristics may in-
clude stereotypic movements (e.g. hand-flapping)
and atypical social development and some features
common to autism spectrum disorder, particular-
ly shyness, limited eye contact, memory problems,
and difficulty with face encoding.
Fragile X syndrome is so-named because of a
microscopically visible Xq27.3 chromosome con-
striction or breakage (the FRAXA fragile site) that
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manifests when patients’ cells are cultured in fo-
late-deficient medium. In 1991, the gene respon-
sible for FXS, FMR1, was identified and the com-
mon mutation was identified as the expansion of
a CGG trinucleotide repeat at the FRAXA frag-
ile site [52, 53]. This was the first known example
of a trinucleotide repeat disorder. The analysis of
the number of CGG repeats and their methylation
status is now the basis for a molecular diagnosis.
In the general population, FMR1 contains up
to 40 CGG repeats. There is also a range of in-
termediate alleles in the range of 41–54 repeats,
not usually associated with instability. Alleles of
55–200 repeats are classified as premutations and
are meiotically unstable. They can expand to yield
slightly larger premutation alleles or they can ex-
pand massively into the full mutation range of
230–4,000 repeats [54]. Expansion of the CGG
repeat to the full mutation results in methyla-
tion that effectively silences the expression of the
FMR1 protein, FMRP, and results in the fragile
X syndrome. Methylation of the FMR1 gene acts
both directly, by inhibiting the binding of tran-
scription factors and indirectly by inducing chro-
matin condensation which, in turn, prevents the
transcription machinery from binding [54].
FMRP binds to a specific population of mRNA
and has an important role in the regulation of pro-
tein synthesis at a local level in the dendrites of
neurons [55]. A proposed role for FMRP at syn-
apses is that it is a negative regulator of protein
synthesis stimulated by group 1 metabotropic glu-
tamate receptor (mGLuR) activation [56] offering
some hope of therapy in pharmaceutical develop-
ment of drugs targeting mGluR5.
Conclusion and Future Perspectives
We have discussed the terminology, classification
and etiology of MR and given a brief review of clas-
sic MR syndromes identified through traditional
avenues of chromosome analysis. Nevertheless,
the chapter must remain in some respects, unfin-
ished. The debate about terminology is ongoing,
although it is hoped that a consensus term that
spans continents can be reached in the not too dis-
tant future. Classification and testing methodolo-
gies also remain controversial. In terms of scientif-
ic knowledge and molecular diagnostic capability,
technology is advancing at an unprecedented rate
and with major impact. As outlined in subsequent
chapters, it is not only improving our understand-
ing of the genetic sub-categories contributing to
the etiology of MR, but it is also shedding light on
the genes linked with newly identified syndromes
as well as elucidating the role of genes in well-rec-
ognized disorders. Indeed, in the new era of next
generation sequencing and resequencing and with
the concept of personalized genomes edging clos-
er, the possibility of testing for genomic changes
involving one or a few base pairs is likely to be
achievable in the not too distant future. In this re-
gard, a single gene disorder that causes non-syn-
dromic MR without any associated dysmorphic
features has recently been described [57] and it
seems likely that many more such genetic causes
of MR will be described in the future.

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