ME64CH31-Shaffer

ARI

ANNUAL
REVIEWS

12 December 2012

21:54

Further

Annu. Rev. Med. 2013.64:441-450. Downloaded from www.annualreviews.org

by b-on: Universidade do Porto (UP) on 04/25/14. For personal use only.

Click here for quick links to

Annual Reviews content online,
including:
Other articles in this volume
Top cited articles
Top downloaded articles
Our comprehensive search

Genetic Basis of Intellectual

Disability
Jay W. Ellison, Jill A. Rosenfeld, and Lisa G. Shaffer
Signature Genomic Laboratories, PerkinElmer, Inc., Spokane, Washington 99207;
email: jay.ellison@perkinelmer.com, jill.mokry@perkinelmer.com, lisagailshaffer@gmail.com

Annu. Rev. Med. 2013. 64:44150

Keywords

First published online as a Review in Advance on

September 27, 2012

microarray analysis, chromosome disorder, next-generation

sequencing, neurodevelopmental phenotypes

The Annual Review of Medicine is online at

med.annualreviews.org
This articles doi:
10.1146/annurev-med-042711-140053
c 2013 by Annual Reviews.
Copyright 
All rights reserved

Abstract
In the past decade, we have witnessed a ood of reports about mutations that cause or contribute to intellectual disability (ID). This rapid
progress has been driven in large part by the implementation of chromosomal microarray analysis and next-generation sequencing methods. The ndings have revealed extensive genetic heterogeneity for ID,
as well as examples of a common genetic etiology for ID and other
neurobehavioral/psychiatric phenotypes. Clinical diagnostic application of these new ndings is already well under way, despite incomplete understanding of non-Mendelian transmission patterns that are
sometimes observed.

441

ME64CH31-Shaffer

ARI

12 December 2012

21:54

INTRODUCTION

Annu. Rev. Med. 2013.64:441-450. Downloaded from www.annualreviews.org

by b-on: Universidade do Porto (UP) on 04/25/14. For personal use only.

Intellectual disability (ID) is the current term

for what was formerly called mental retardation. The designation mental retardation still
frequently appears in print, but there is international consensus on the use of intellectual
disability, although it, too, may be replaced in
the future (1). The World Health Organization currently denes ID as . . .a signicantly
reduced ability to understand new or complex
information and to learn and apply new skills
(impaired intelligence). This results in a reduced ability to cope independently (impaired
social functioning), and begins before adulthood, with a lasting effect on development (2).
Another denition, provided by the American
Association of Intellectual and Developmental
Disability, is a disability characterized by
signicant limitations both in intellectual functioning and in adaptive behavior, which covers
many everyday social and practical skills. This
disability originates before the age of 18 (3). A
commonly used cutoff for a limitation in intellectual functioning is an intelligence quotient
(IQ) below 70. ID is estimated to affect 1%3%
of the population in Western societies (4),
and the monetary burden is high: the Centers
for Disease Control and Prevention estimated
that the cost to care for those born in the year
2000 with ID will total $51.2 billion over their
lifetimes (5).
ID can be caused by environmental insults
such as infection, trauma, and teratogens,
but a sizable proportion is caused by genetic
abnormalities. Still, 60% of cases of ID
do not have a known etiology (6). Rapid
progression of new technologies, such as
whole-genome sequencing, promises to increase understanding of the etiology of ID
by identifying genes and mechanisms that
contribute to its development. In this review,
we address the following: (a) known genetic
causes of ID, including classes of mutations and
their relative frequencies when determined;
(b) the divergent neurodevelopmental phenotypes associated with mutations in some genes;
and (c) the inheritance patterns observed for the

442

Ellison

Rosenfeld

Shaffer

susceptibility to ID, including highly penetrant

Mendelian patterns, oligo/polygenic modes
of transmission, and sporadic cases due to de
novo mutations. We do not attempt to provide
exhaustive lists but instead focus on recent and
current trends in research into genetic aspects
of ID.

VISIBLE AND SUBMICROSCOPIC

CHROMOSOMAL CAUSES
Approximately 15% of ID is attributable to
cytogenetically visible abnormalities, with at
least two-thirds of these cases accounted for
by trisomy 21 (46). Other microscopically
visible causative alterations include deletions,
translocations (usually unbalanced), and supernumerary marker chromosomes. Traditional
chromosome analysis is limited to the identication of abnormalities of 510 million
base pairs (Mb) or larger. Smaller genomic
alterations require molecular methods, such as
genomic microarrays, for their detection.
The use of microarrays has led to the
identication of numerous pathogenic gains
and losses of chromosomal segments that previously escaped detection by light microscopy.
A number of recent reviews document the
growing number of copy number alterations
associated with ID, often leading to the
designation of new clinical syndromes (710).
Current estimates are that approximately 15%
20% of cases of ID are due to submicroscopic
copy number variants (CNVs) (7, 1113).
In a number of instances, the gene or genes
responsible for the developmental abnormality
have been identied through their location
in the critical regions of pathogenic CNVs
(1419). Identication of these genes has in
some cases led to the detection of mutations in
affected individuals who do not have the CNV,
thus adding to the list of single-gene causes
of ID.
The additional yield of diagnoses provided
by microarray analysis over that of karyotype
is illustrated by the case of an unbalanced
translocation involving chromosomes 1 and 14

ME64CH31-Shaffer

ARI

12 December 2012

21:54

Chromosome 1

Annu. Rev. Med. 2013.64:441-450. Downloaded from www.annualreviews.org

by b-on: Universidade do Porto (UP) on 04/25/14. For personal use only.

50.00 Mb

1p31.1

100.00 Mb

1q12

150.00 Mb

200.00 Mb

1q43

1q41

Material from 14q32 on derivative chromosome 1

Chromosome 14
14p12

14p11.2

25.00 Mb
14q12

14q21.3

50.00 Mb

14q23.1

75.00 Mb

14q24.3

14q31.3

14q32.2

Figure 1
Microarray and idiogram characterization of an unbalanced 1;14 translocation. In a two-month-old female referred for developmental
delay and seizure disorder, oligonucleotide-based array comparative genomic hybridization (aCGH) showed a 4.4-Mb terminal
deletion of the short arm of chromosome 1 (blue highlighted region on aCGH results) and a 3.5-Mb terminal duplication of the long arm
of chromosome 14 ( pink highlighted region on aCGH results). Fluoresence in situ hybridization (FISH; not shown) conrmed this to be
an unbalanced translocation. The idiograms represent the chromosome complement of the proband, with a derivative chromosome 1
showing the deletion of 1p36 and presence of material from 14q32, a normal chromosome 1, and two normal chromosomes 14.
Monosomy 1p36 is the most common subtelomeric deletion syndrome in our population and is characterized by intellectual disability,
usually severe, and typical dysmorphic facial features in all affected individuals, with additional congenital anomalies and seizures in a
majority. Because this child also has extra material from the long arm of chromosome 14, it is likely that she also manifests additional
clinical features not found in monosomy 1p36 syndrome.

(Figure 1). The imbalance reected a replacement of a segment in 1p by a similarly sized

segment derived from 14q. Such a change is
below the limit of resolution of karyotype,
but was clearly evident following microarray
analysis, as shown in the gure.

SINGLE-GENE CAUSES
One of the best-known single genes causing
ID is FMR1, in which mutations lead to
fragile X syndrome (2022). It was the rst
of many X-linked ID genes to be identied,
and it remains the most common single-gene
www.annualreviews.org Genetic Basis of Intellectual Disability

443

ARI

12 December 2012

21:54

etiology of ID, with an estimated incidence of

1 in 5,000 males (thus accounting for 0.5%
of cases of ID) (23). Another notable X-linked
gene is MECP2, originally implicated in Rett
syndrome and since found to be causative for
several ID phenotypes that affect both males
and females (24). Identication of a large
number of X-linked ID genes was facilitated
by the characteristic inheritance pattern and
the availability of pedigrees for linkage analysis
(25), as well as the collaborative efforts of
international consortia (26). More recently,
the number of ID-associated X-linked genes
has further grown through the implementation
of high-throughput sequencing technologies
(27). As of this writing, the number of identied
X-linked genes leading to ID is >100 (28).
Until next-generation sequencing methods
came into use a few years ago, only a handful of
autosomal genes were known to be associated
with ID. That number is changing so rapidly
that this review will likely be outdated by the
time it reaches print. Multiple strategies have
been employed to identify the culpable genes.
Besides the characterization of genes in CNVs
(see, e.g., 1517), an approach that uses nextgeneration sequencing methods has proven
successful in identifying pathogenic genes and
strong candidates. This approach is illustrated
by the report of Vissers et al., who performed
exome sequencing for ten individuals with
moderate to severe ID and a negative family
history of the phenotype (29). The hypothesis
was that at least some of the patients were
affected because of de novo mutations, which
were sought through the sequencing of affected
patients and their parents (trio analysis). In
addition to one maternally inherited mutation
in a known X-linked ID gene, they found nine
de novo mutations, two of which involved
genes known to cause ID (one X-linked and one
autosomal dominant). Of the remaining seven
genes, four have functions suggestive of roles in
neurodevelopment. This suggestive evidence
included interactions of the encoded proteins
with known neurodevelopmental genes (two
cases) and a mouse knockout model that has
neural tube defects (one case); the fourth gene

Annu. Rev. Med. 2013.64:441-450. Downloaded from www.annualreviews.org

by b-on: Universidade do Porto (UP) on 04/25/14. For personal use only.

ME64CH31-Shaffer

444

Ellison

Rosenfeld

Shaffer

has a putative role in granule cell development

in the central nervous system. Two reports
of mutations in one of these four candidates
(DYNC1H1) have subsequently been found
in additional individuals with ID (30, 31). A
similar approach was taken by Need et al.,
who performed exome sequencing for twelve
trios, eight of which involved developmental
delay/ID in the proband. They reported likely
causal variants in ve of these eight cases; four
of the alterations were de novo, and in the fth
case, biallelic inherited mutations were found
(32). These studies indicate that the approach
of trio sequence analysis in cases of ID without
a family history is sure to reveal additional
genes with causal roles in ID.
A strategy for identifying autosomal recessive single-gene causes of ID uses autozygosity
mapping in consanguineous families with multiple affected offspring. In these studies, linkage
analysis was carried out to identify candidate
genomic intervals, and sequence analysis was
then performed, either on candidate genes by
traditional sequencing methods or by using
exome capture techniques coupled with nextgeneration sequence analysis (33, 34). In the
largest such report, involving 136 families (34),
homozygous mutations were found in 23 genes
known to be associated with ID and/or other
neurologic disorders. In addition, mutations
were observed in 50 novel genes (two of the
genes had different mutations in two families
each). Validation of the causative role of these
genes awaits conrmatory studies in other
cohorts, and for the time being they should be
formally considered as candidates for playing
roles in intellectual development. Still, a
number of these genes are quite attractive candidates, based on their brain-specic functions
and/or interactions with known ID-causative
genes.
In this review, we do not attempt to catalog
every report of single-gene mutations leading
to ID but rather focus on current trends in gene
discovery strategies. It is too early to tell what
proportion of ID is attributable to mutations in
single genes because many of the examples represent extremely rare disorders, and verication

ME64CH31-Shaffer

ARI

12 December 2012

21:54

Annu. Rev. Med. 2013.64:441-450. Downloaded from www.annualreviews.org

by b-on: Universidade do Porto (UP) on 04/25/14. For personal use only.

in additional cases is needed. One current estimate for the total number of single genes
contributing to ID is >450 (A. Schenck, personal communication); in time, the total could
well reach the thousands. In the coming few
years, as widespread sequencing studies attempt
to validate the many identied candidates and
give incidence numbers for known culprits, the
extent of the locus heterogeneity of Mendelian
and X-linked forms of ID, and their aggregate contribution to the phenotype, will be
apparent.

FUNCTIONS OF GENES
ASSOCIATED WITH
INTELLECTUAL DISABILITY
As the number of genes associated with ID
has grown, many authors have searched for
trends regarding the functions of the proteins encoded by these genes. One biologic
function that is often mentioned is that of
synapse formation and transmission (29,
3538). It is clear, however, that diverse
cellular functions are affected by mutations in
genes linked to ID. These functions include
transcriptional and translational control,
protein modication, chromatin remodeling, differentiation of neural and supporting
cells of the nervous system, and centrosome
function (29, 34, 3840).
There is a growing list of examples
where knowledge of the function of proven
causative ID genes can help assess the potential
pathogenicity of newly identied candidates.
This analysis typically uses two related pieces of
knowledge: specic physiologic pathways and
interacting protein partners. If the protein encoded by a newly implicated candidate gene is
known to interact with the protein produced by
an acknowledged pathogenic ID gene, the candidate becomes more attractive as a contributor
to the phenotype. The likelihood of causative
involvement is also increased if the candidate
gene operates in a pathway that contains one or
more bona de pathogenic genes. Examples of
this type of inferential evidence are reviewed by
Kaufman et al. (41).

COMMON ETIOLOGY
OF INTELLECTUAL
DISABILITY AND OTHER
NEURODEVELOPMENTAL
PHENOTYPES
There is great phenotypic variability in individuals with ID, not only in IQ levels but also
with respect to other neurologic and neurobehavioral manifestations. For example, a significant fraction of individuals with ID have been
shown to meet diagnostic criteria for autism;
in the most recent study, this proportion was
28% (42). Conversely, an even higher fraction
of individuals with autism have been shown to
have ID (43). This co-occurrence of clinical features is reected in the ndings of individual
genes or CNVs that can cause one or the other
phenotype (or both) in different individuals
(44).
As the use of genomic microarray analysis
for the evaluation of individuals with psychiatric diseases grows, it has become clear that
some of the same CNVs that lead to ID in
some patients are associated with psychiatric
disorders such as schizophrenia in others (45,
reviewed in 46). The variable phenotypes exhibited by individuals with alterations in known
ID-causing genes extend to other neurodevelopmental disorders, including bipolar disorder,
attention decithyperactivity disorder, and
epilepsy. The involved genes are too numerous
to list here, but examples can be found in several
recent reviews and reports (36, 41, 44, 4749).
The basis for this type of variable expressivity
is not known, but possible explanations include
modifying alleles in the individuals genetic
background, somatic mutations and/or epigenetic events, environmental exposures, and
stochastic processes. The latter are likely to
be especially important during development of
the nervous system, as discussed by Mitchell
(50). Further research involving the relevant
pathways and players, in addition to continued
genotypephenotype analysis, promises to
enhance our understanding of the pathophysiology of neurocognitive and neuropsychiatric
disorders.

www.annualreviews.org Genetic Basis of Intellectual Disability

445

ME64CH31-Shaffer

ARI

12 December 2012

21:54

INHERITANCE OF GENETIC
SUSCEPTIBILITY

Annu. Rev. Med. 2013.64:441-450. Downloaded from www.annualreviews.org

by b-on: Universidade do Porto (UP) on 04/25/14. For personal use only.

One of the earliest comprehensive genetic analyses of ID was conducted by Lionel Penrose,
who published his work in the 1938 monograph
A Clinical and Genetic Study of 1280 Cases
of Mental Defect (51). His study included not
only clinical evaluation of individuals with varying degrees of ID but also detailed examination
and evaluation of immediate and extended
family members. He was aware of well-known
Mendelian disorders such as phenylketonuria,
TaySachs disease, and tuberous sclerosis,
but a key contribution came from his analysis
of familial clustering of cases without known
causes. Two major ndings were that the
risk of mental defect to family members of
a proband was signicant and that this risk
decreased greatly with decreasing relatedness.
He also observed that the risk to family members was greater for more mildly affected cases.
He acknowledged the possible explanations of
de novo mutations, multifactorial inheritance,
and incomplete penetrance to account for the
non-Mendelian segregation of the phenotype
in many families. These same themes are still
pertinent today, as we discuss in the following
paragraphs.
A seeming paradox is the relatively high
prevalence of ID given the reproductive
disadvantage of affected individuals. A partial
explanation could be that an appreciable
fraction of cases have an autosomal recessive
etiology, so that pathogenic alleles maintain
their signicant frequency in unaffected carriers. There are not reliable estimates on what
proportion of ID such cases represent, in part
because in Western societies (where most of the
research has been done), family size is limited
and singleton cases appear to be sporadic. The
recent identication of candidate genes for recessive ID, and imminent testing of these genes
in large populations, should help determine
their aggregate contribution to the mutational
spectrum of ID cases. Another explanation
for the observed frequency of ID is that many
cases may be due to de novo mutationseither

446

Ellison

Rosenfeld

Shaffer

CNVs or point mutations in single genes.

The high yield of presumed pathogenic de
novo mutations in the small studies of Vissers
et al. (29) and Need et al. (32) suggests that
a signicant fraction of sporadic cases will be
accounted for by de novo mutations (5254).
The vast majority of recent studies that
identify causative or candidate genes for ID
have involved cases of moderate to severe ID,
and the study protocols are typically designed
to ascertain highly penetrant pathogenic alleles.
Still unaccounted for are the majority of cases
of mild to moderate ID, the category for which
familial clustering is most often observed.
It is generally assumed that intelligence is a
continuous trait (like height or blood pressure),
and that mild ID represents the lower end of
the IQ spectrum. Such continuous traits, as
well as other common conditions such as heart
disease and diabetes, are most often thought
to be multifactorial/polygenic in nature, with
multiple alleles each producing a small effect.
Multifactorial/polygenic models can explain
non-Mendelian segregation patterns and reduced penetrance, phenomena that are evident
in family studies of idiopathic ID and that are
often observed for cases of ID associated with
CNVs. But multifactorial models of common
disorders have been questioned recently, as
genome-wide association studies have revealed
only a small fraction of the observed heritability
for such conditions (reviewed in 55).
Although traditional multifactorial models
may not be able to explain the non-Mendelian
familial transmission of many cases of ID, there
is recent evidence that a related concept likely
operates in at least some instances. Girirajan
et al. (56) showed that expressivity and penetrance of a neurodevelopmental phenotype
associated with a 16p12.1 microdeletion were
strongly affected by the presence of additional
large CNVs. They used the term two-hit to explain the effect of the co-occurring CNVs, but
oligogenic or polygenic would also be appropriate descriptors. In another recent report,
Schaaf et al. used the term oligogenic heterozygosity to describe their ndings in which
probands with autism were much more likely

Annu. Rev. Med. 2013.64:441-450. Downloaded from www.annualreviews.org

by b-on: Universidade do Porto (UP) on 04/25/14. For personal use only.

ME64CH31-Shaffer

ARI

12 December 2012

21:54

than controls to carry multiple heterozygous

variants in autism susceptibility genes (57).
The above two examples illustrate that the
dichotomy between single-gene and polygenic
etiologies is often arbitrary and in fact is
probably inappropriate (58), and it is belied
by the well-recognized concept of modier
genes. Modifying alleles by denition affect
the expressivity and penetrance of single-gene
disorders, and their presence could thus explain
the non-Mendelian transmission patterns often
observed for ID, even if de novo alterations
and recessive mutations turn out to be involved
in the majority of cases. In fact, for the latter
examples, there are scant data on the penetrance of the phenotype other than for CNVs,
although one report (34) mentions 12 variants
that did not cosegregate with ID. It is worth
pointing out that the current approach of
searching for de novo mutations (trio analysis)
seems to make it more difcult to identify alleles
that are associated with dominant inheritance
and incomplete penetrance. This is because
if a nonmanifesting parent carries a reducedpenetrance allele that leads to the phenotype
in the offspring, that variant will likely be
removed by the ltering process of the analysis.
Before sequence analysis is implemented on
a large scale in a clinical diagnostic setting, a key

issue needs to be considered: the penetrance associated with mutations in individual genes. A
high penetrance value lends condence to the
conclusion that a mutation is contributing to
the phenotype of a given affected individual,
and for asymptomatic individuals and prenatal
cases, penetrance is a measure of the predictive
value of the test. Figures for penetrance represent averages for large numbers of carriers, but
for a given patient the value is inuenced by
the particular set of modifying alleles present.
Therefore, to derive the maximum diagnostic
and predictive utility from clinical sequencing
tests, it seems important to identify these modifying alleles. The pool of candidates for modifying genes is huge: it includes hundreds of known
causative or candidate genes that have recently
been identied, in addition to the genes encoding their interacting protein partners and
other proteins in implicated physiologic pathways. Identication of modifying alleles should
be achievable through large-scale sequencing
studies of patients, family members, and unrelated controls, especially if detailed phenotypic
analysis of controls and relatives of affected individuals is performed. It seems reasonable to
envision that in a few years we will be able to
paint a much clearer picture of the genetic etiology of ID for families with affected individuals.

SUMMARY POINTS
1. There is tremendous genetic heterogeneity for ID, with hundreds of genes already known
to contribute to the phenotype.
2. Technological advances such as genomic microarray analysis and next-generation sequencing have contributed to the recent rapid progress in gene identication.
3. Genes associated with intellectual disability are also involved in the pathogenesis of other
neurobehavioral/neuropsychiatric phenotypes.
4. Despite recent progress in gene discovery, the fraction of cases of ID that is explainable
is still small.

FUTURE ISSUES
1. Large studies in patient cohorts and controls are needed to validate candidate genes and
estimate the penetrance levels for mutations in individual genes.

www.annualreviews.org Genetic Basis of Intellectual Disability

447

ME64CH31-Shaffer

ARI

12 December 2012

21:54

2. The same large studies should help answer questions about major genes and modiers
i.e., the monogenic versus polygenic nature of genetic etiologies of ID.
3. Animal models should be useful to help elucidate the pathophysiology of ID and other
associated phenotypes.

DISCLOSURE STATEMENT
The authors are employees of Signature Genomic Laboratories, PerkinElmer, Inc.

ACKNOWLEDGMENTS
Annu. Rev. Med. 2013.64:441-450. Downloaded from www.annualreviews.org
by b-on: Universidade do Porto (UP) on 04/25/14. For personal use only.

The authors thank A. Michelle Caldwell, BS (Signature Genomic Laboratories), for preparation
and editing of the manuscript.

LITERATURE CITED
1. Salvador-Carulla L, Bertelli M. 2008. Mental retardation or intellectual disability: time for a conceptual change. Psychopathology 41:1016
2. World Health Organization: Regional Ofce for Europe. 2010. Denition: intellectual disability. http://
www.euro.who.int/en/what-we-do/health-topics/noncommunicable-diseases/mental-health/
news/news/2010/15/childrens-right-to-family-life/definition-intellectual-disability
3. American Association on Intellectual and Developmental Disabilities (AAIDD). 2010. Overview of intellectual disability: denition, classication, and systems of support. Presented at AAIDD Annu. Meet., Providence,
RI, June 811. http://www.aaidd.org/media/PDFs/CoreSlide.pdf
4. Leonard H, Wen X. 2002. The epidemiology of mental retardation: challenges and opportunities in the
new millennium. Ment. Retard. Dev. Disabil. Res. Rev. 8:11734
5. Centers for Disease Control and Prevention. 2004. Economic costs associated with mental retardation,
cerebral palsy, hearing loss, and vision impairmentUnited States, 2003. Morb. Mortal. Wkly. Rep. 53:57
59
6. Rauch A, Hoyer J, Guth S, et al. 2006. Diagnostic yield of various genetic approaches in patients with
unexplained developmental delay or mental retardation. Am. J. Med. Genet. Part A 140:206374
7. Cooper GM, Coe BP, Girirajan S, et al. 2011. A copy number variation morbidity map of developmental
delay. Nat. Genet. 43:83846
8. Kaminsky EB, Kaul V, Paschall J, et al. 2011. An evidence-based approach to establish the functional and
clinical signicance of copy number variants in intellectual and developmental disabilities. Genet. Med.
13:77784
9. Vissers LE, de Vries BB, Veltman JA. 2010. Genomic microarrays in mental retardation: from copy
number variation to gene, from research to diagnosis. J. Med. Genet. 47:28997
10. Morrow EM. 2010. Genomic copy number variation in disorders of cognitive development. J. Am. Acad.
Child Adolesc. Psychiatry 49:1091104
11. Zahir F, Friedman JM. 2007. The impact of array genomic hybridization on mental retardation research:
a review of current technologies and their clinical utility. Clin. Genet. 72:27187
12. Miller DT, Adam MP, Aradhya S, et al. 2010. Consensus statement: Chromosomal microarray is a rsttier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am. J.
Hum. Genet. 86:74964
13. Hochstenbach R, van Binsbergen E, Engelen J, et al. 2009. Array analysis and karyotyping: workow
consequences based on a retrospective study of 36,325 patients with idiopathic developmental delay in
the Netherlands. Eur. J. Med. Genet. 52:16169
448

Ellison

Rosenfeld

Shaffer

Annu. Rev. Med. 2013.64:441-450. Downloaded from www.annualreviews.org

by b-on: Universidade do Porto (UP) on 04/25/14. For personal use only.

ME64CH31-Shaffer

ARI

12 December 2012

21:54

14. Lugtenberg D, Veltman JA, van Bokhoven H. 2007. High-resolution genomic microarrays for X-linked
mental retardation. Genet. Med. 9:56065
15. Talkowski ME, Mullegama SV, Rosenfeld JA, et al. 2011. Assessment of 2q23.1 microdeletion syndrome
implicates MBD5 as a single causal locus of intellectual disability, epilepsy, and autism spectrum disorder.
Am. J. Hum. Genet. 89:55163
16. Durand CM, Betancur C, Boeckers TM, et al. 2007. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat. Genet. 39:2527
17. Koolen DA, Kramer JM, Neveling K, et al. 2012. Mutations in the chromatin modier gene KANSL1
cause the 17q21.31 microdeletion syndrome. Nat. Genet. 44:63941
18. Ballif BC, Rosenfeld JA, Traylor R, et al. 2012. High-resolution array CGH denes critical regions and
candidate genes for microcephaly, abnormalities of the corpus callosum, and seizure phenotypes in patients
with microdeletions of 1q43q44. Hum. Genet. 131:14556
19. Zollino M, Orteschi D, Murdolo M, et al. 2012. Mutations in KANSL1 cause the 17q21.31 microdeletion
syndrome phenotype. Nat. Genet. 44:63638
20. Pieretti M, Zhang FP, Fu YH, et al. 1991. Absence of expression of the FMR-1 gene in fragile X syndrome.
Cell 66:81722
21. Fu YH, Kuhl DP, Pizzuti A, et al. 1991. Variation of the CGG repeat at the fragile X site results in genetic
instability: resolution of the Sherman paradox. Cell 67:104758
22. Verkerk AJ, Pieretti M, Sutcliffe JS, et al. 1991. Identication of a gene (FMR-1) containing a CGG
repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell
65:90514
23. Coffee B, Keith K, Albizua I, et al. 2009. Incidence of fragile X syndrome by newborn screening for
methylated FMR1 DNA. Am. J. Hum. Genet. 85:50314
24. Christodoulou J, Ho G. 2001 (updated 2009). MECP2-related disorders. In GeneReviews, ed. RA
Pagon, TD Bird, CR Dolan, et al., 1993. Seattle: Univ. Washington. http://www.ncbi.nlm.nih.gov/
books/NBK1497/
25. Ropers HH, Hamel BC. 2005. X-linked mental retardation. Nat. Rev. Genet. 6:4657
26. Ropers HH. 2010. Genetics of early onset cognitive impairment. Annu. Rev. Genomics Hum. Genet. 11:161
87
27. Tarpey PS, Smith R, Pleasance E, et al. 2009. A systematic, large-scale resequencing screen of
X-chromosome coding exons in mental retardation. Nat. Genet. 41:53543
28. Lubs HA, Stevenson RE, Schwartz CE. 2012. Fragile X and X-linked intellectual disability: four decades
of discovery. Am. J. Hum. Genet. 90:57990
29. Vissers LE, de Ligt J, Gilissen C, et al. 2010. A de novo paradigm for mental retardation. Nat. Genet.
42:110912
30. Willemsen MH, Vissers LEL, Willemsen MAAP, et al. 2012. Mutations in DYNC1H1 cause severe
intellectual disability with neuronal migration defects. J. Med. Genet. 49:17983
31. Weedon MN, Hastings R, Caswell R, et al. 2011. Exome sequencing identies a DYNC1H1 mutation in
a large pedigree with dominant axonal Charcot-Marie-Tooth disease. Am. J. Hum. Genet. 89:30812
32. Need AC, Shashi V, Hitomi Y, et al. 2012. Clinical application of exome sequencing in undiagnosed
genetic conditions. J. Med. Genet. 49:35361
33. Kuss AW, Garshasbi M, Kahrizi K, et al. 2011. Autosomal recessive mental retardation: Homozygosity
mapping identies 27 single linkage intervals, at least 14 novel loci and several mutation hotspots. Hum.
Genet. 129:14148
34. Najmabadi H, Hu H, Garshasbi M, et al. 2011. Deep sequencing reveals 50 novel genes for recessive
cognitive disorders. Nature 478:5763
35. Melom JE, Littleton JT. 2011. Synapse development in health and disease. Curr. Opin. Genet. Dev.
21:25661
36. Guilmatre A, Dubourg C, Mosca AL, et al. 2009. Recurrent rearrangements in synaptic and neurodevelopmental genes and shared biologic pathways in schizophrenia, autism, and mental retardation. Arch.
Gen. Psychiatry 66:94756
37. Hamdan FF, Gauthier J, Araki Y, et al. 2011. Excess of de novo deleterious mutations in genes associated
with glutamatergic systems in nonsyndromic intellectual disability. Am. J. Hum. Genet. 88:30616
www.annualreviews.org Genetic Basis of Intellectual Disability

449

ARI

12 December 2012

21:54

38. Bolduc FV, Tully T. 2009. Fruit ies and intellectual disability. Fly (Austin) 3:91104
39. Hu H, Eggers K, Chen W, et al. 2011. ST3GAL3 mutations impair the development of higher cognitive
functions. Am. J. Hum. Genet. 89:40714
40. Thornton GK, Woods CG. 2009. Primary microcephaly: Do all roads lead to Rome? Trends Genet.
25:50110
41. Kaufman L, Ayub M, Vincent JB. 2010. The genetic basis of non-syndromic intellectual disability: a
review. J. Neurodev. Disord. 2:182209
42. Bryson SE, Bradley EA, Thompson A, et al. 2008. Prevalence of autism among adolescents with intellectual
disabilities. Can. J. Psychiatry 53:44959
43. Fombonne E. 2003. Epidemiological surveys of autism and other pervasive developmental disorders: an
update. J. Autism Dev. Disord. 33:36582
44. Mefford HC, Batshaw ML, Hoffman EP. 2012. Genomics, intellectual disability, and autism. N. Engl. J.
Med. 366:73343
45. Walsh T, McClellan JM, McCarthy SE, et al. 2008. Rare structural variants disrupt multiple genes in
neurodevelopmental pathways in schizophrenia. Science 320:53943
46. Malhotra D, Sebat J. 2012. CNVs: harbingers of a rare variant revolution in psychiatric genetics. Cell
148:122341
47. Zoghbi HY, Warren ST. 2010. Neurogenetics: advancing the next-generation of brain research. Neuron
68:16573
48. Sebat J, Levy DL, McCarthy SE. 2009. Rare structural variants in schizophrenia: one disorder, multiple
mutations; one mutation, multiple disorders. Trends Genet. 25:52835
49. Malhotra D, McCarthy S, Michaelson JJ, et al. 2011. High frequencies of de novo CNVs in bipolar
disorder and schizophrenia. Neuron 72:95163
50. Mitchell KJ. 2007. The genetics of brain wiring: from molecule to mind. PLoS Biol. 5:e113
51. Penrose LS. 1938. A clinical and genetic study of 1280 cases of mental defect. London: H.M. Stationery Off.
159 pp.
52. Lupski JR. 2010. New mutations and intellectual function. Nat. Genet. 42:103638
53. Robinson PN. 2010. Whole-exome sequencing for nding de novo mutations in sporadic mental retardation. Genome Biol. 11:144
54. Huang K. 2011. De novo paradigm: the ultimate answer to the paradox in mental retardation? Clin. Genet.
79:42728
55. Mitchell KJ. 2012. What is complex about complex disorders? Genome Biol. 13:237
56. Girirajan S, Rosenfeld JA, Cooper GM, et al. 2010. A recurrent 16p12.1 microdeletion supports a two-hit
model for severe developmental delay. Nat. Genet. 42:2039
57. Schaaf CP, Sabo A, Sakai Y, et al. 2011. Oligogenic heterozygosity in individuals with high-functioning
autism spectrum disorders. Hum. Mol. Genet. 20:336675
58. Badano JL, Katsanis N. 2002. Beyond Mendel: an evolving view of human genetic disease transmission.
Nat. Rev. Genet. 3:77989

Annu. Rev. Med. 2013.64:441-450. Downloaded from www.annualreviews.org

by b-on: Universidade do Porto (UP) on 04/25/14. For personal use only.

ME64CH31-Shaffer

450

Ellison

Rosenfeld

Shaffer

ME64-frontmatter

ARI

18 December 2012

10:19

Annu. Rev. Med. 2013.64:441-450. Downloaded from www.annualreviews.org

by b-on: Universidade do Porto (UP) on 04/25/14. For personal use only.

Contents

Annual Review of
Medicine
Volume 64, 2013

Abiraterone and Novel Antiandrogens: Overcoming Castration

Resistance in Prostate Cancer
R. Ferraldeschi, C. Pezaro, V. Karavasilis, and J. de Bono p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1
Antibody-Drug Conjugates in Cancer Therapy
Eric L. Sievers and Peter D. Senter p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p15
Circulating Tumor Cells: From Bench to Bedside
Marija Balic, Anthony Williams, Henry Lin, Ram Datar, and Richard J. Cote p p p p p p p p p31
Cytokines, Obesity, and Cancer: New Insights on Mechanisms Linking
Obesity to Cancer Risk and Progression
Candace A. Gilbert and Joyce M. Slingerland p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p45
Glioblastoma: Molecular Analysis and Clinical Implications
Jason T. Huse, Eric Holland, and Lisa M. DeAngelis p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p59
Harnessing the Power of the Immune System to Target Cancer
Gregory Lizee, Willem W. Overwijk, Laszlo Radvanyi, Jianjun Gao,
Padmanee Sharma, and Patrick Hwu p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p71
Human Papillomavirus Vaccines Six Years After Approval
Alan R. Shaw p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p91
Reduced-Intensity Hematopoietic Stem Cell Transplants for
Malignancies: Harnessing the Graft-Versus-Tumor Effect
Saar Gill and David L. Porter p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 101
The Need for Lymph Node Dissection in Nonmetastatic
Breast Cancer
Catherine Pesce and Monica Morrow p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 119
The Role of Anti-Inammatory Drugs in Colorectal Cancer
Dingzhi Wang and Raymond N. DuBois p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 131
The Human Microbiome: From Symbiosis to Pathogenesis
Emiley A. Eloe-Fadrosh and David A. Rasko p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 145
The Rotavirus Saga Revisited
Alan R. Shaw p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 165
v

ME64-frontmatter

ARI

18 December 2012

10:19

Staphylococcal Infections: Mechanisms of Biolm Maturation and

Detachment as Critical Determinants of Pathogenicity
Michael Otto p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 175
Toward a Universal Inuenza Virus Vaccine: Prospects and Challenges
Natalie Pica and Peter Palese p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 189
Host Genetics of HIV Acquisition and Viral Control
Patrick R. Shea, Kevin V. Shianna, Mary Carrington,
and David B. Goldstein p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 203

Annu. Rev. Med. 2013.64:441-450. Downloaded from www.annualreviews.org

by b-on: Universidade do Porto (UP) on 04/25/14. For personal use only.

Systemic and Topical Drugs for the Prevention of HIV Infection:

Antiretroviral Pre-exposure Prophylaxis
Jared Baeten and Connie Celum p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 219
Hyperaldosteronism as a Common Cause of Resistant Hypertension
David A. Calhoun p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 233
Mechanisms of Premature Atherosclerosis in Rheumatoid
Arthritis and Lupus
J. Michelle Kahlenberg and Mariana J. Kaplan p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 249
Molecular Mechanisms in Progressive Idiopathic Pulmonary Fibrosis
Mark P. Steele and David A. Schwartz p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 265
Reprogrammed Cells for Disease Modeling and Regenerative Medicine
Anne B.C. Cherry and George Q. Daley p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 277
Application of Metabolomics to Diagnosis of Insulin Resistance
Michael V. Milburn and Kay A. Lawton p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 291
Defective Complement Inhibitory Function Predisposes
to Renal Disease
Anuja Java, John Atkinson, and Jane Salmon p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 307
New Therapies for Gout
Daria B. Crittenden and Michael H. Pillinger p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 325
Pathogenesis of Immunoglobulin A Nephropathy: Recent Insight
from Genetic Studies
Krzysztof Kiryluk, Jan Novak, and Ali G. Gharavi p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 339
Podocyte Biology and Pathogenesis of Kidney Disease
Jochen Reiser and Sanja Sever p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 357
Toward the Treatment and Prevention of Alzheimers Disease:
Rational Strategies and Recent Progress
Sam Gandy and Steven T. DeKosky p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 367
Psychiatrys Integration with Medicine: The Role of DSM-5
David J. Kupfer, Emily A. Kuhl, Lawson Wulsin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 385

vi

Contents

ME64-frontmatter

ARI

18 December 2012

10:19

Update on Typical and Atypical Antipsychotic Drugs

Herbert Y. Meltzer p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 393
Ataluren as an Agent for Therapeutic Nonsense Suppression
Stuart W. Peltz, Manal Morsy, Ellen M. Welch, and Allan Jacobson p p p p p p p p p p p p p p p p p p 407
Treating the Developing Brain: Implications from Human Imaging
and Mouse Genetics
B.J. Casey, Siobhan S. Pattwell, Charles E. Glatt, and Francis S. Lee p p p p p p p p p p p p p p p p p p 427

Annu. Rev. Med. 2013.64:441-450. Downloaded from www.annualreviews.org

by b-on: Universidade do Porto (UP) on 04/25/14. For personal use only.

Genetic Basis of Intellectual Disability

Jay W. Ellison, Jill A. Rosenfeld, and Lisa G. Shaffer p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 441
Sickle Cell Disease, Vasculopathy, and Therapeutics
Adetola A. Kassim and Michael R. DeBaun p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 451
Duty-Hour Limits and Patient Care and Resident Outcomes: Can
High-Quality Studies Offer Insight into Complex Relationships?
Ingrid Philibert, Thomas Nasca, Timothy Brigham, and Jane Shapiro p p p p p p p p p p p p p p p p p 467
Quality Measurement in Healthcare
Eliot J. Lazar, Peter Fleischut, and Brian K. Regan p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 485
Indexes
Cumulative Index of Contributing Authors, Volumes 6064 p p p p p p p p p p p p p p p p p p p p p p p p p p p 497
Article Titles, Volumes 6064 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 501
Errata
An online log of corrections to Annual Review of Medicine articles may be found at
http://med.annualreviews.org/errata.shtml

Contents

vii

Annual Reviews
Its about time. Your time. Its time well spent.

New From Annual Reviews:

Annual Review of Statistics and Its Application

Volume 1 Online January 2014 http://statistics.annualreviews.org

Editor: Stephen E. Fienberg, Carnegie Mellon University

Annu. Rev. Med. 2013.64:441-450. Downloaded from www.annualreviews.org

by b-on: Universidade do Porto (UP) on 04/25/14. For personal use only.

Associate Editors: Nancy Reid, University of Toronto

Stephen M. Stigler, University of Chicago
The Annual Review of Statistics and Its Application aims to inform statisticians and quantitative methodologists, as
well as all scientists and users of statistics about major methodological advances and the computational tools that
allow for their implementation. It will include developments in the field of statistics, including theoretical statistical
underpinnings of new methodology, as well as developments in specific application domains such as biostatistics
and bioinformatics, economics, machine learning, psychology, sociology, and aspects of the physical sciences.

Complimentary online access to the first volume will be available until January 2015.
table of contents:

What Is Statistics? Stephen E. Fienberg

A Systematic Statistical Approach to Evaluating Evidence
from Observational Studies, David Madigan, Paul E. Stang,
Jesse A. Berlin, Martijn Schuemie, J. Marc Overhage,
Marc A. Suchard, Bill Dumouchel, Abraham G. Hartzema,
Patrick B. Ryan

High-Dimensional Statistics with a View Toward Applications

in Biology, Peter Bhlmann, Markus Kalisch, Lukas Meier
Next-Generation Statistical Genetics: Modeling, Penalization,
and Optimization in High-Dimensional Data, Kenneth Lange,
Jeanette C. Papp, Janet S. Sinsheimer, Eric M. Sobel

The Role of Statistics in the Discovery of a Higgs Boson,

David A. van Dyk

Breaking Bad: Two Decades of Life-Course Data Analysis

in Criminology, Developmental Psychology, and Beyond,
Elena A. Erosheva, Ross L. Matsueda, Donatello Telesca

Brain Imaging Analysis, F. DuBois Bowman

Event History Analysis, Niels Keiding

Statistics and Climate, Peter Guttorp

Statistical Evaluation of Forensic DNA Profile Evidence,

Christopher D. Steele, David J. Balding

Climate Simulators and Climate Projections,

Jonathan Rougier, Michael Goldstein
Probabilistic Forecasting, Tilmann Gneiting,
Matthias Katzfuss
Bayesian Computational Tools, Christian P. Robert
Bayesian Computation Via Markov Chain Monte Carlo,
Radu V. Craiu, Jeffrey S. Rosenthal
Build, Compute, Critique, Repeat: Data Analysis with Latent
Variable Models, David M. Blei
Structured Regularizers for High-Dimensional Problems:
Statistical and Computational Issues, Martin J. Wainwright

Using League Table Rankings in Public Policy Formation:

Statistical Issues, Harvey Goldstein
Statistical Ecology, Ruth King
Estimating the Number of Species in Microbial Diversity
Studies, John Bunge, Amy Willis, Fiona Walsh
Dynamic Treatment Regimes, Bibhas Chakraborty,
Susan A. Murphy
Statistics and Related Topics in Single-Molecule Biophysics,
Hong Qian, S.C. Kou
Statistics and Quantitative Risk Management for Banking
and Insurance, Paul Embrechts, Marius Hofert

Access this and all other Annual Reviews journals via your institution at www.annualreviews.org.

Annual Reviews | Connect With Our Experts

Tel: 800.523.8635 (us/can) | Tel: 650.493.4400 | Fax: 650.424.0910 | Email: service@annualreviews.org