The Comorbidity of Autism with the Genomic Disorders of Chromosome 15q11.2-q13
A cluster of low copy repeats on the proximal long arm of chromosome 15 mediates various forms of stereotyped deletions and duplication events that cause a group of neurodevelopmental disorders that are associated with autism or autism spectrum disorders (ASD). The region is subject to genomic imprinting and the behavioral phenotypes associated with the chromosome 15q11.2-q13 disorders show a parent-of-origin specific effect that suggests that an increased copy number of maternally derived alleles contributes to autism susceptibility. Notably, nonimprinted, biallelically expressed genes within the interval also have been shown to be misexpressed in brains of patients with chromosome 15q11.2-q13 genomic disorders, indicating that they also likely play a role in the phenotypic outcome. This review provides an overview of the phenotypes of these disorders and their relationships with ASD and outlines the regional genes that may contribute to the autism susceptibility imparted by copy number variation of the region.
The comorbidity of autism with the genomic disorders of chromosome 15q11.2-q13
, David Wu
, Janine M. LaSalle
, N. Carolyn Schanen
Department of Medical Microbiology and Immunology, University of California, Davis, CA 95616, USA
Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA
Nemours Biomedical Research, Alfred I duPont Hospital for Children, Wilmington, DE 19803, USA
Department of Pediatrics, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, USA
abstracta r t i c l e i n f o
Received 20 May 2008
Accepted 5 August 2008
Available online xxxx
Autism spectrum disorders
Interstitial duplication chromosome 15
Isodicentric chromosome 15
Low copy repeats
A cluster of low copy repeats on the proximal long arm of chromosome 15 mediates various forms of
stereotyped deletions and duplication events that cause a group of neurodevelopmental disorders that are
associated with autism or autism spectrum disorders (ASD). The region is subject to genomic imprinting and
the behavioral phenotypes associated with the chromosome 15q11.2-q13 disorders show a parent-of-origin
speciﬁc effect that suggests that an increased copy number of maternally derived alleles contributes to
autism susceptibility. Notably, nonimprinted, biallelically expressed genes within the interval also have been
shown to be misexpressed in brains of patients with chromosome 15q11.2-q13 genomic disorders, indicating
that they also likely play a role in the phenotypic outcome. This review provides an overview of the
phenotypes of these disorders and their relationships with ASD and outlines the regional genes that may
contribute to the autism susceptibility imparted by copy number variation of the region.
© 2008 Elsevier Inc. All rights reserved.
The complexities of the genomic landscape of chromosome 15q11.2-q13 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
The deletion syndromes and autism spectrum disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Prader–Willi syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Angelman syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
The duplication syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Interstitial duplication and triplications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Isodicentric chromosome 15. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Molecular characteristics of the duplications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Prevalence of duplications of chromosome 15 in autism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Neurologically relevant 15q11.2-13 genes with altered expression in 15q11.2-q13 deletions and duplications . . . . . . . . . . . . . . . . . . . . 0
UBE3A and ATP10A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
SNRPN and snoRNAs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
NECDIN and MAGEL2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
receptor subunit genes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
CYFIP1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Epigenetic factors regulating 15q11.2-q13 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Nuclear organization and homologous pairing of 15q11.2-q13 alleles in human neurons. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Neurobiology of Disease xxx (2008) xxx–xxx
⁎ Corresponding author. Nemours Biomedical Research, 1600 Rockland Road, Room RC1-241, Wilmington, DE 19803, USA. Fax: +302 651 6767.
E-mail address: firstname.lastname@example.org (N.C. Schanen).
Available online on ScienceDirect (www.sciencedirect.com).
YNBDI-01730; No. of pages: 11; 4C: 2
0969-9961/$ – see front matter © 2008 Elsevier Inc. All rights reserved.
Contents lists available at ScienceDirect
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The complexit ies of the genomic landscape of chromosome
Chromosome 15 has been identiﬁed as one of seven chromosomes
enriched in segmental low copy repeats (LCRs) or duplicons (Bailey
et al., 2002). These duplicons provide a mechanism in which LCR-
mediated misalignment during meiosis I leads to unequal nonallelic
homologous recombination generating a series of common break-
points (BPs) along the 15q11.2-q13 (Christian et al., 1999; Robinson
et al., 1993a,c, 1998b).
The proximal three BP correspond to complex LCRs ranging in size
from 50–400 kb and contain sequences derived from HERC2 and
GOLGA8E loci (Amos-Landgraf et al., 1999; Ji et al., 2000; Makoff and
Flomen, 2007)(Fig. 1). While the actively transcribed HERC2 and
GOLGA8E genes lie just centromeric to BP3 and BP1, respectively,
numerous transcribed pseudogenes derived from these loci can be
found in the vicinity of BP1, BP2 and BP3. Two more distal BP clusters
(BP4 and BP5) involve a distinct set of LCRs that have limited sequence
homology to the repeats at BP1–BP3. These paired LCRs are roughly
500 kb in length and oriented head to head, which may facilitate the
U-type crossover events that generate isodicentric chromosomes
(Makoff and Flomen, 2007).
The complex structure and orientation of the LCRs on proximal
15q, which include both tandem and inverted repeats, contribute to a
variety of rearrangements that are often stereotyped, with common
blocks of genomic material that is either deleted or duplicated.
Deletions of the region lead to two phenotypically distinct neurode-
velopmental disorders, Prader–Willi syndrome (PWS) and Angelman
syndrome (AS), which have different phenotypes due to the effect of
an imprinted domain between BP2 and BP3 (Buiting et al., 1995; Knoll
et al., 1989). This gene rich region is under the control of a bi-partite
imprinting center that directs expression of a number of genes that
show parent-of-origin speciﬁc expression (reviewed in Horsthemke
and Buiting, 2006). Notably, imprinted expression of some of these
genes is limited to the nervous system, while some genes encode
neuron-speciﬁc transcripts (Albrecht et al., 1997; Chibuk et al., 2001;
Lee et al., 2003). Individuals with duplications of 15q11.2-q13 also
demonstrate parent-of-origin differences in phenotypes, as mater-
nally derived duplications pose the greater risk for ASD, suggesting
that the autism susceptibility allele(s) at chromosome 15q11.2-q13
may be subject to imprinting.
The deletion syndromes and autism spectrum disorders
PWS is classically characterized by hypotonia and failure to thrive
in infancy, which evolves into a complex neurobehavioral phenotype
accompa nied by cognitive impairment, hyperphagia leading to
obesity, obsessive compulsive behaviors that include hoarding and
skin picking, with an increased risk of autism spectrum disorders
(ASD). In addition, patients with PWS typically have hypogonadism,
dysmorphic facial features, small hands and feet and may be
hypopigmented (reviewed in Cassidy et al., 2000). In the majority of
cases, PWS arises by deletions on the paternal chromosome 15, either
between BP1–2 (Class I) or BP2–BP3 (Class 2). Approximately 25% of
patients wit h PWS have uniparental diso my for the maternal
chromosome, which can be either isodisomic or heterodisomic
(Fridman and Koiffmann, 2000). The remaining patients have
imprinting errors on the paternal homolog of chromosome 15,
which lead to aberrant methylation of the PWS imprinting center
and downregulation of paternally expressed transcripts (Nicholls and
h several paternally expressed genes are known–MKRN3,
MAGEL2, NDN, SNURF-SNRPN and more than seventy C/D box small
nucleolar RNA genes–it is still uncertain whether a single gene or
several genes are responsible for the PWS phenotype. Notably, while
each of the different molecular classes of PWS lead to loss of paternally
expressed genes, they have differential effects on the biallelic and
maternally expressed transcripts in the region, which are likely to
contribute to differences in phenotypes. Genotype–phenotype studies
in PWS patients in various molecular groups have indicated that the
Fig. 1. Schematic of chromosome 15q11.1-13.3 showing the position of known genes based on the UCSC genome browser. Maternally expressed transcripts highlighted in red, and
paternally expressed transcripts in black. The HERC2 gene is highlighted in blue and the GOLGA8E gene is highlighted in green. (Below) The relative positions of the 5 BP clusters are
shown below with sequence homology indicated by color, blue indicating regions of homology to HERC2 and green indicating regions of homology to GOLGA8E. The black and white
hatching indicates a heteromorphic region near the centromere that includes a number of pseudogenes and can expand in the normal population. At least one HERC2 based repeat
lies in this region. The track above the breakpoint schematic shows the density of SNP coverage for this region on the Affymetrix 6.0 whole genome array with notable gaps at the
positions of the common BPs, although not all probes for detecting copy number variations are shown in the UCSC browser. The region included in Class I and Class II deletions/
duplications is indicated by the black bars at the bottom with the position of the small duplication identiﬁed by Weiss et al. (2008) also noted. Similarly, the region encompassed by
the two most common forms of idic(15) chromosomes is indicated with solid blue line indicating a region of tetrasomy and dashed line indicating trisomy.
2 A. Hogart et al. / Neurobiology of Disease xxx (2008) xxx–xxx
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deletion patients tend to be the most severe in presentation, both in
terms of degree of learning impairment and frequency of aberrant
behaviors, (Dykens and Cassidy, 1995). Notably, within the deletion
group, those with class I deletions (BP1:BP3) have been found to have
more signiﬁcant impairments in adaptive behaviors than those with
class 2 (BP2:BP3) deletions, suggesting a role of one or more of the
four genes that lie with the BP1–BP2 interval (Butler et al., 2004;
Milner et al., 2005).
Studies of patients with maternal UPD reveal that, while they may
appear milder on some outcome measures, they are more likely than
patients with deletions to manifest ASD, with studies estimating the
comorbidity of ASD in PWS to be between 19–36.5% (Descheemaeker
et al., 2006; Milner et al., 2005; Veltman et al., 2004). Notably, in the
study conducted by Veltman et al., (2004), no signiﬁcant difference in
the frequency of subjects meeting the diagnostic threshold for ASD
was noted in the UPD vs. the deletion groups. However, among the
UPD patients, scores were signiﬁcantly higher on the autism screening
questionnaire applied, with deﬁcits in social interaction driving the
differences between groups. Similarly, Descheemeaecker et al. (2006)
examined a cohort of PWS pa tients for eviden ce of pervasive
developmental disorders (PDD) using the PDD-mental retardation
scale screening questionnaire. While they found a somewhat lower
incidence of PDD among their cohort than reported by Veltman (19%
vs 36.5%), similar increases in scores were identiﬁed for the UPD
subgroup and no evidence for an IQ effect on the incidence of PDD was
detected (i.e. the frequency of PDD was the same for subjects with
IQ b 70 and N 70). Taken together, these studies suggest that there is an
increased risk of ASD imparted by the UPD form of PWS and implicate
maternally expressed transcripts in the pathogenesis of the ASD
Additionally, patients with PWS are at increased risk of other
neuropsychiatric disorders including affective and psychotic disorders
(Descheemaeker et al., 2006; Milner et al., 2005; Veltman et al., 2005a,
2004). It is intriguing that it is also the UPD form of PWS that poses the
greater risk for psychiatric disease in adole sc ence and young
adulthood (Boer et al., 2002). A recent study of 119 patients with
PWS revealed a prevalence of psychiatric symptoms of 64% in patients
with PWS arising from maternal UPD as compared to 28.2% in the
deletion cases. The disorders appear to be primarily affective disorders
with a high incidence of psychotic symptoms (Soni et al., 2008) or
primary psychoses (Vogels et al., 2004). In some cases, there appeared
to be an evolution in the behavioral phenotype, with psychotic
disorders developing in individuals who had been diagnosed with
PDD in childhood (Descheemaeker et al., 2002).
Patients with AS have severe to profound mental retardation,
microcephaly, seizures, ataxia and may also show hypopigmentation
(Cassidy et al., 2000). They almost always lack speech and language is
typically severely impaired with function at a level less than 2 years
age equivalent (Andersen et al., 2001; Penner et al., 1993; Peters et al.,
2004b). Socially, patients with AS are notable for their happy
demeanors, a propensity for easy smiling and laughter and are
engaging with both adults and children, making excellent eye contact
and frequent social bids for communication despite the absence of
expressive language (Oliver et al., 2007). AS most often arises from
deletions that occur through the LCR at BP1, 2 and 3, with the critical
region for AS lying just 35 kb telomeric to the PWS critical region
Lalande and Calciano, 2007).
A subset of patients with AS
have paternal uniparental disomy and an approximately 10% of
patients have imprinting errors on the maternal chromosome, with
demethylation of the PWS imprinting center and expression of
paternal transcripts from both chromosomes. In AS, a single gene of
major effect has been identiﬁed, UBE3A, which shows imprinted
expression in selected neuronal populations (Hoffman, 1997; Kishino
et al., 1997; Matsuura et al., 1997). Point mutations in UBE3A occur in
roughly 10% of patients with this disorder (Fang et al., 1999). Notably,
genotype–phenotype relationships have been less well-established in
AS, although it appears that the deletion and UBE3A mutation groups
are most severely affected in terms of cognition, seizure frequency and
hypopigmentation, while patients with UPD and imprinting muta-
tions are more likely to attain limited speech and have fewer seizures
(Burger et al., 1996; Lossie et al., 2001).
AS is often described as falling within the autism spectrum and
studies have suggested a high prevalence of comorbidity of ASD in AS
(Bonati et al., 2007; Peters et al., 2004a; Steffenburg et al., 1996).
However, these studies must be interpreted cautiously as the severity
of the cognitive and language impairment in AS poses a major
confound, as mental ages are typically less than 18–24 months
(Andersen et al., 2001; Peters et al., 2004b). Trillingsgaard and
Østergaard (200 4) investigated the comorbidity of autism in 16
patients with AS using the Autism Diagnostic Observation Scale-
generic (ADOS-G) (Lord et al., 1989), which revealed that 13/16
subjects met algorithm criteria for ASD (Trillingsgaard and Ostergaard,
2004). However, co mparison of the social and com munication
interactions of the AS patients with those of a cohort of patients
with idiopathic autism led the authors to conclude that the disabilities
in the social and communication domains that underlie the ASD
diagnosis in the AS group are better deﬁned by developmental delay,
rather than a speciﬁc deﬁcit in social and communication skills as is
typical in autism. The children simply had not reached a mental age at
which reciprocal interactions and skills such as joint attention and
pointing would be expected to emerge. This argument is supported by
studies showing that children with AS are more likely to initiate and
maintain social contact than similarly cognitively impaired children
(Oliver et al., 2007), and that they are ﬂexible in their beha -
viors (Didden et al., 2007). Hence, the degree of cognitive impair-
ment in AS may lead to an overestimate of ASD using standard
diagnostic measures in this group of patients (Trillingsgaard and
The duplication syndromes
Interstitial duplications of proximal 15q11.2-13 often appear to be
the reciprocal events of the PWS/AS deletions with LCR-mediated
recombinations occurring through BP1–3 or BP2–3(Repetto et al.,
1998). However, more distal LCR also contribute with some duplica-
tion chromosomes and interstitial duplications and triplications
extending to BP4 and BP5 (Wandstrat et al., 1998). In addition,
duplications of this region can occur via U-type crossover events in
meiosis (Robinson et al., 1998a), leading to the formation of a
supernumerary derivative chromosome 15 that has two centromeres
called an isodicentric chromosome 15 or idic(15) [also previously
inverted duplication 15] (Fig. 2). Like PWS and AS, there appears
to be a parent-of-origin effect on phenotype, with maternally
inherited duplications posing the most clear-cut risk for ASD (Cook
et al., 1997).
Interstitial duplication and triplications
Patients with maternal ly derived interstitial duplications of
chromosome 15 present with a neurodevelopmental disorder that
frequently includes autism or ASD (Bolton et al., 2001; Browne et al.,
1997; Cook et al., 1997; Mao et al., 2000; Repetto et al., 1998; Roberts
et al., 2002). The ASD phenotype does not appear fully penetrant,
however, as not all patients with maternally derived duplications
meet even the broad criteria for ASD using standardized measures of
diagnosis (Boyar et al., 2001). The behavioral phenotype is complex
with anxiety, emotional lability, tantrums and hyperactivity posing
signiﬁcant challenges for caregivers (Thomas et al., 1999). Dysmorphic
features are infrequent and growth is typically normal, however
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hypotonia is common in infancy and gross and ﬁne motor delays
occur. Seizures, hypogonadism, gait abnormalities and episodes of
unprovoked laughter have also been reported (Browne et al., 1997;
Repetto et al., 1998; Thomas et al., 1999). Speech and language delays
are prominent and speech apraxia, developmental language disorder
and dyslexia also have been reported (Boyar et al., 2001; Cook et al.,
1997). Additional features that have been identiﬁed in isolated cases
have included cryptorchidism, cardiac malformations and juvenile
rheumatoid arthritis, (Thomas et al., 1999).
Familial cases suggest that paternally-derived duplications are
associated with a more normal phenotype, as a number of seemingly
unaffected mothers have transmitted paternally-derived duplication
chromosomes to their children (Browne et al., 1997; Cook et al., 1998;
Roberts et al., 2002). There are, however, reports of paternally-derived
duplications associated with developmental disorders, which in at
least one family, has included autism or ASD in affected siblings (Mao
et al., 2000; Mohandas et al., 1999; Veltman et al., 2005b). Given that
this was a single family, the possibility that this was a coincident
occurrence of ASD in a family with a duplication cannot be excluded.
Nonetheless, based on a limited number of cases reported, the
phenotype associated with de novo paternally-derived duplications
appears to be widely variable — ranging from apparently normal to
signiﬁcantly cognitively impaired, with language and social deﬁcits
(Mo handas et al., 1999; Veltman et al., 2005 b) and behaviors
reminiscent of PWS (Mao et al., 2000). The basis for the discrepancies
in phenotype is unclear, and given the relatively small number of
cases, it is premature to make conclusions that paternally-derived
duplications are benign.
By contrast, both maternally and paternally-derived interstitial
triplications appear to be consistently associated with more severe
neurodevelopmental phenotype, which includes hypotonia, global
developmental delays with speciﬁc deﬁcits in speech and language,
severe mental retardation, and seizures (Cassidy et al., 1996; Clayton-
Smith et al., 1993; Dennis et al., 2006; Long et al., 1998; Ungaro et al.,
2001; Vialard et al., 2003). In addition, autism or ASD has been
identiﬁed in several of these cases (Cassidy et al., 1996; Vialard et al.,
2003), and behaviors suggestive of ASD are described in reports that
did not include formal assessments for autism (Dennis et al., 2006).
Both PWS-like (Dennis et al., 2006; Long et al., 1998; Pettigrew et al.,
1987) and AS-like features (Ungaro et al., 2001) have been described,
and curiously the PWS-like phenotype occurred in individual patients
whose duplication chromosomes were either maternally (Dennis
et al., 2006; Long et al., 1998) or paternally (Pettigrew et al., 1987)
derived. The small number of these cases precludes distinction of clear
phenotypic diffe rences between those carrying maternally and
paternally-derived duplication chromosomes. Nonetheless, the pre-
sence of ASD among the handful of paternally-derived interstitial
triplication cases is of interest in terms of mechanisms that may
underlie the predisposition to this aspect of the phenotype.
Isodicentric chromosome 15
As a general rule, patients with maternal ly derived idic(15)
chromosomes that include the PWS/AS region present with similar
clinical traits as those with interstitial rearrangements, albeit to a
greater degree, suggesting that increasing dosage of the duplicated
segment has an adverse effect on phenotype. Hypotonia in infancy is
pronounced and may lead to genetic evaluation for PWS, revealing the
idic(15) chromosome (Battaglia
et al., 1997). In addition, patients with
idic(15) frequently have minor dysmorphic features including a short
upturned nose, downslanting palpebral ﬁssures, high arched palate,
incompletely folded ears and full lips (Abeliovich et al., 1995; Abuelo
et al., 1995; Buoni et al., 1999; Dennis et al., 2006; Grammatico et al.,
1994; Mignon et al., 1996; Rineer et al., 1998; Robinson et al., 1993b;
Wolpert et al., 2000b). Notably, these are often subtle, and may be
missed in infancy. Various congenital anomalies have been reported in
individual cases, although genitourinary malformations, joint laxity,
strabismus, cortical visual impairment and hyperpigmentation have
been seen in multiple cases suggesting that they may be part of the
phenotype of this disorder. A few cases of hexasomy for chromosome
15q11.2-q13 have been identiﬁed. These children were severely
affected with profound mental retardation and intractable epilepsy
and more prominent dysmorphic features including myopathic facies,
downslanting palpebral ﬁssures and low set ears (Huang and Bartley,
2003; Mann et al., 2004; Nietzel et al., 2003; Qumsiyeh et al., 2003).
Patients with idic(15) consistently show signiﬁcant developmental
delays, including gross motor and ﬁne delays, and cognitive impair-
ment, which ranges from moderate to severe (Crolla et al., 1995;
Fig. 2. Schematic of the genomic rearrangements of chromosome 15. The ideogram of chromosome 15 is shown in the middle. On the left hand side, interstitial rearrangements are
shown. On the far left, PWS and AS can arise by deletion of 15q11.2-q13.1. Alternatively, this region can be duplicated, shown here as a tandem duplication of the BP1:BP3 region.
These lead to trisomy of the involved segments of DNA. On the right, the two most common forms of idic(15) associated with ASD are shown, Class 3B and Class 5A. The Class 3B
duplications lead to tetrasomy of the involved segments of DNA, while in the class 5A idic(15) chromosomes, there is tetrasomy for the region through BP4 and trisomy for the interval
between BP4 and BP5.
4 A. Hogart et al. / Neurobiology of Disease xxx (2008) xxx–xxx
ARTICLE IN PRESS
Dennis et al., 2006; Webb et al., 1998). Like the children with
interstitial rearrangements, growth parameters are typically normal
although both microcephaly and macrocephaly have been described
(Webb et al., 1998; Wolpert et al., 2000b). Seizures, including infantile
spasms, complicate the clinical course for at least half of the patients
(Battaglia et al., 1997; Bingham et al., 1996; Rineer et al., 1998) and
intractable epilepsy occurs in some patients with associated regres-
sion in skills (Mann et al., 2004 and Schanen, unpublished). Behavioral
problems, including impulsivity, self-injurious and aggressive and/or
self-injurious behaviors, hyperactivity and anxiety appear in early
childhood and often increase in adolescence (Webb et al., 1998;
Wolpert et al., 2000a,b). In addition, a number of sudden, unexplained
deaths among seemingly healthy individuals with idic(15) have been
recently identiﬁed as well as deaths in patients with idic(15) who
manifest a chronic degenerative phenotype associated with relentless
seizures (Schanen and Cook, in preparation).
Although the phenotype arising from duplication of proximal 15q
is complex, the disorder has gained considerable attention over recent
years because these duplication chromosomes pose a substantial risk
for ASD. In our ongoing study of duplications of chromosome 15 in
autism, we found that 44 of 54 subject s (81% ) with idic(15)
chromosomes met strict criteria for autism using the combined
Autism Diagnostic Interview—Revised (Lord et al., 1994) and ADOS-G
criteria (Lord et al., 1989), with an additional six cases (92%) meeting
the broader ASD criteria on one or both measures (Schanen,
unpublished). This is consistent with data from Rineer et al. (1998),
who used the Gilliam Autism Rating Scale (GARS) (Gilliam, 1995) to
characterize the autistic symptoms in a cohort of children and adults
with idic(15). In subjects over age 5 years, 20/21 had autism quotient
scores above 90, suggesting a high probability of being autistic (Rineer
et al., 1998). Notably, some regression in socialization appears to be
part of the phenotype, as infants and toddlers with idic(15) often
appear more social and make better eye contact and vocalize more
than they do as older children (Borgatti et al., 2001; Mohandas et al.,
1999; Rineer et al., 1998; Wolpert et al., 2000a,b). Similar to the
concern with AS, there is some concern that ASD may be overcalled in
the lowest functioning cases of idic(15), who have mental ages under
18 months, again younger that many of the social behaviors emerge.
Speech and language delays are universal but variable in severity, with
characteristic autistic speech traits such as delayed echolalia, pronoun
reversal and stereotyped utterances populating the vocalizations of
verbal children and adults with idic(15), while many lack functional
speech (Borgatti et al., 2001; Clayton-Smith et al., 1993; Grammatico
et al., 1994; Maggouta et al., 2003; Rineer et al., 1998; Wolpert et al.,
2000b). Socialization is impaired in idic(15) with decreased eye
contact and lack of reciprocity. They also typically display numerous
repetitive and stereotyped behaviors (rocking, hand ﬂapping, licking)
that are often directed toward sensory stimulation (Borgatti et al.,
2001; Wolpert et al., 2000a,b). Notably, while it appears that subjects
with idic(15) and ASD display core autistic traits, it is likely that there
are behavioral characteristics enriched in this population that can
distinguish them from other forms of autism that may provide a
behavioral signature for ASD arising from the susceptibility locus on
proximal 15q. Clearly, more detailed studies of the natural history of
this disorder are warranted in order to fully deﬁne the behavioral
proﬁle of children with idic(15) chromosomes.
Molecular characteristics of the duplications
Cytogenetic, molecular and array comparative genomic hybridiza-
tion based examination of duplication chromosomes has revealed that
the interstitia l duplications can arise throu gh both int ra- and
interchromosomal recombination exchanges through the LCR clus-
tered on proximal 15q (Robinson et al., 1998a). Like the PWS/AS
deletions, Class I and Class 2 duplications occur, which vary in their
proximal boundary and thus inclusion of the genes between BP1 and
BP2 (Table 1 and
The distal boundary for most interstitial
duplications appears to reside at BP3, while in interstitial triplications,
the distal BP may lie at BP4 or BP5 (Wandstrat et al., 1998). Both
tandem and inverted duplication even ts have been recognized
(Robinson et al., 1998a).
Idic(15) chromosomes that include the PWS/AS region are almost
exclusively maternal in origin, with rare paternal cases occurring in
mosaic form in association with the UPD form of PWS (Baumer et al.,
2001; Saitoh et al., 2007). A number of different structural forms have
been identiﬁed that can be classiﬁed by their distal BP position
(Table 1). Class 1 and 2 idic(15) chromosomes, deﬁned as idic(15) that
do not hybridize with probes to the PWS/AS critical region, are small,
heterochromatic derivative chromosomes that appear to have no
phenotypic consequences. Interestingly, they have been reported in
association with UPD in patients with PWS and AS, suggesting they
may lead to meiotic segregation errors (Robinson et al., 1993d).
Notably, Class 2 idic(15) chromosomes, which would include the
genes between BP1 and BP2 have not been speciﬁcally described,
however it is intriguing to consider the possibility that they might
have phenotypic consequences given the proposed role of genes in the
interval in development and the differences in phenotype in Class I
versus Class 2 PWS deletion patients and the observation that CYFIP1
was overexpressed in lymphoblasts from patients with larger idic(15)
chromosomes (Butler et al., 2004; Nishimura et al., 2007). Most of the
Classiﬁcation of deletion and duplication chromosomes
Proximal BP Distal BP BP1–BP2 dosage BP2:BP3 dosage BP3:BP4 dosage BP4:BP5 dosage
Class 1 1 3 1 1 2 2
Class 2 2 3 2 1 2 2
Class 1 1 3 3 3 2 2
Class 2 2 3 2 3 2 2
Class 1 1 1 2 2 2 2
Class 2A 1 2 3 2 2 2
Class 2B 2 2 4 2 2 2
Class 3A 2 3 4 3 2 2
Class 3B 3 3 4 4 2 2
Class 4A 3 4 4 4 3 2
Class 4B 4 4 4 4 4 2
Class 5A 4 5 4 4 4 3
Class 5B 5 5 4 4 4 4
Class 6 Variable Variable Variable Variable Variable Variable
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ARTICLE IN PRESS
idic(15) identiﬁed in association with neurodevelopmental disorders
fall into the remaining classes, with Classes 3B and 5A being the
predominant forms (Fig. 2)(Wang et al., 2004). Class 3B idic(15)
chromosomes are symmetric, extending to BP3 on each end and result
in tetrasomy for the genomic region encompassed by the duplication
chromosome. Roughly half of the idic(15) chromosomes characterized
by array CGH fell into this class (Sahoo et al., 2005; Wang et al., 2004).
Class 5 idic(15) arise through BP5 exchanges, and the asymmetric
form (Class 5A; BP4:BP5) appear to be other major form of idic(15)
chromosome, again accounting for almost half of the cases in the
study by Wang et al. (2004). Class 6 idic(15) chromosomes are atypical
rearrangements that involve non-LCR based BP (Wang et al., 20 04,
2008). While it is likely that this structural variability impacts
phenotypic outcome, each of these molecular groups is associated
with cognitive impairment, seizures and risk for ASD, suggesting that
the genes that are the major contributors to those aspects of the
phenotype lie in the region shared by most duplication chromosomes.
The basis for the extreme bias in identiﬁcation of maternally
derived idic(15) chromosomes remains enigmatic. Likely explanations
include a combination of a tendency for the meiotic error to occur in
the maternal germline, an ascertainment bias based severity of
symptoms arising from maternal duplications and perhaps selection
against paternally-derived idic(15) chromosomes in early develop-
ment potentially through pregnancy loss or loss of the idic(15)
chromosome. Rare cases of paternally-derived interstitial triplications
implies that paternal trisomy for the PWS/AS region is not lethal
(Browne et al., 1997; Cassidy et al., 1996; Mao et al., 2000; Mohandas
et al., 1999; Ungaro et al., 2001) although further investigation is
required to fully understand the consequences of excess paternal
Prevalence of duplications of chromosome 15 in autism
Systematic screening for chromosomal abnormalities in cohorts of
patients with autism using cytogenetic and array-based strategies has
revealed that copy number variation (CNV) at this region contributes
signiﬁcantly to the etiology of ASD (Christian et al., 2008; Schroer
et al., 1998; Sebat et al., 2007). Most estimates of prevalence fall in the
0.5–3% range, depending on the criteria used for sample ascertain-
ment and method used for identifying the duplications (Browne et al.,
1997; Cook et al., 1997; Schroer et al., 1998; Sebat et al., 2007; Weiss
et al., 2008). The likelihood of identifying a duplication clearly
increases if the patient is also signiﬁcantly cognitively impaired and
has gross motor delays and/or seizures. Notably, interstitial duplica-
tions are being increasingly recognized with the use of array-based
strategies for diagnosis of CNV in children with developmental
disorders. In addition, both typical and smaller, atypical duplications
have been identiﬁed using high resolution tools to assess CNV among
well characterized autism samples that have been widely used for
linkage studies (Sebat et al., 2007; Szatmari et al., 2007; Ullmann et al.,
2007; Weiss et al., 2008).
Neurologically relevant 15q11.2-13 genes with altered expression
in 15q11.2-q13 deletions and duplications
While the 13 MB region encompassed by the scope of 15q11.2-q13
deletion and duplication syndromes contains at least 30 characterized
genes, the overwhelming focus of gene expression studies has been on
the genes showing imprinted expression, as these are presumably the
most likely to show parent-of-origin speciﬁc gene expression
differences. The smallest of the regional duplications detected by
CNV analysis includes only the ATP10A and GABRB3 genes, implicating
them as critical genes for the ASD phenotype, although the data needs
to be interpreted cautiously (Weiss et al., 2008). In light of recent
results showing that nonimprinted GABA
receptor genes (GABRB3,
GABRA5, GABRG3) from 15q11.2-q13 can show parental expression
differences in the absence of a normal biparental contribution (Hogart
et al., 2007), the expectation of maternal only expression alterations
may need to be reexamined. In this section, several of the imprinted
and noni mprinted genes likely to have pathologically relevant
dysregulation in 15q11.2-q13 duplications and ASD are discussed.
UBE3A and ATP10A
The maternally expressed UBE3A encodes an ubiquitin E3 ligase
enzyme that directs ubiquitin molecules transferred from E1 and E2
pathway enzymes to speciﬁc substrates (Ciechanover et al., 1994).
UBE3A loss of function mutations or de ﬁciency due to maternal
deletion or imprinting mutation cause AS (Kishino et al., 1997;
Matsuura et al., 1997; Moncla et al., 1999) and engineered Ube3a
mutations in mouse models recapitulate several features of
AS, in cluding motor dysfunction and hippocampal impairments
(Jiang et al., 1998; Miura et al., 2002). A Drosophila model of dUBE3A
overexpression identiﬁed a novel downstream target Rho-GEF
Pbl/ECT2 that showed abnormal cellular localization in mutant
mouse brain (Reiter et al., 2006). UBE3A was shown to be transcrip-
tionally active from the duplication chromosome in lymphocytes
(Herzing et al., 2002) and overexpression of UBE3A is also observed in
15q11.2-q13 maternal duplication lymphoblast samples (Baron et al.,
2006). These results from 15q11.2-q13 duplication cell lines suggest
that increased UBE3A expression is likely also to occur in the brains of
these patients, but the phenotypic consequences are currently
unclear. PWS cortical tissues with maternal UPD express twice the
normal level of UBE3A compared to controls (Hogart et al., 2007) and
PWS UPD patients have more autistic behaviors than those with
paternal 15q11.2-q13 deletions (Descheemaeker et al., 2006; Milner
et al., 2005; Veltman et al., 2004). These combined results suggest that
gene dosage directed UBE3A overexpression in 15q11.2-q13 duplica-
tions could have a major impact on the ASD phenotype.
ATP10A encodes a type IV P-type ATPase that when maternally
deleted in mice leads to obesity and type II diabetes (Dhar et al., 2004).
While maternal inheritance of the obesity phenotype implies that
Atp10a is imprinted, discrepancies in imprinting in different mouse
strains suggests that imprinting of Atp10a may be less robust than
Ube3a and potentially dependent on genetic modiﬁers (Kashiwagi
et al., 2003; Kayashima et al., 2003a,b). In humans, ATP10A is proposed
to be imprinted similarly to UBE3A
et al., 2001), however
imprinting was also observed in lymphoblasts from patients with AS
(Meguro et al., 2001), unlike the biallelic expression in blood observed
for UBE3A (Sutcliffe et al., 1997). While some genetic association data
suggests that ATP10A may contribute to autism (Nurmi et al., 2003a), a
causative role for ATP10A in th e pathogenesis of 15q11.2-q13
chromosome disorders remains to be proven.
SNRPN and snoRNAs
The SNRPN locus on chromosome 15q11.2-q13 encodes highly
complex paternally expressed imprinted transcripts that extend from
upstream of the SNRPN promoter throughout UBE3A in the antisense
orientation (Landers et al., 2004; Runte et al., 2001). The 5′ end of
SNRPN contains the imprinting center involved in marking the
ma ternal and pa ternal chromosomes through differential DNA
methylation (Sutcliffe et al., 1994). Two small spliceosome proteins,
SNURF and SmN, small nucleoprotein N, encoded by the 5′ exons,
(Gray et al., 1999) have minimal inﬂuence on the phenotype of PWS, as
mice with disruptions of the protein are phenotypically normal
(Bressler et al., 2001; Yang et al., 1998). Splicing of downstream
noncoding exons produces several classes of small nucleolar RNAs
(snoRNAs) (Runte et al., 2001) that are proposed to be involved in
mRNA processing of neurologically relevant genes including the
serotonin receptor 2C (Cavaillé et al., 2000; Kishore and Stamm, 2006).
Mice with deletions of the cluster of MBII-85 snoRNA sequences
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ARTICLE IN PRESS
(orthologous to human HBII-85) within the large SNRPN transcript
exhibit early post-natal growth deﬁciencies and late-onset hyperpha-
gia suggesting that these noncoding RNAs contribute to the phenotype
of PWS (Ding et al., 2008; Skryabin et al., 2007).
NECDIN and MAGEL2
NECDI N (NDN) and the related gene MAGEL2 are paternally
expressed imprinted genes primarily expressed in pos t-mitotic
neurons (Jay et al., 1997; Lee et al., 2000, 2005). The mouse knockout
model of Ndn has shown conﬂicting results as one model yielded early
post-natal lethality due to respiratory distress, while another Ndn
deﬁcient mouse failed to display any apparent phenotypes (Gérard
et al., 1999; Tsai et al., 1999). Elimination of Magel2 in mice results in
neonatal growth deﬁciencies, metabolic abnormalities, and altera-
tions in activity, food intake, and fertility (Bischof et al., 2007). While
neither of these genes seems to fully account for the phenotypes
observed in PWS, it is clear that expression abnormalities of these
genes could have profound effects on many neurological processes
including respiration and circadian outputs.
receptor subunit genes
GABA, the major inhibitory neurotransmitter in the brain, func-
tions to hyperpolarize the membrane through binding to ionotropic
receptors. Chromosome 15q11.2-q13 contains
receptor subunit genes (GABR), GABRB3, GABRA5, and
GABRG3 that are normally biallelically expressed in mouse and human
(Buettner et al., 2004; Hogart et al., 2007; Nicholls, 1993). Although
the 15q11.2-q13 GABR genes are not imprinted, the increased severity
of PWS and AS deletion patients compared to UPD patients (Varela
et al., 2004, 2005) implicates a role for GABR genes in these disorders.
Mice lacking Gabra5 and Gabrg3 appear normal (Culiat et al., 1994),
while Gabrb3 knockout mice have profound neurological phenotypes
including seizures, sleep abnormalities, hyperactivity, hypersensitivity
to touch stimuli, learning and memory deﬁcits, and defects in social
and exploratory behaviors (DeLorey et al., 1998; DeLorey et al., 2008;
Hashemi et al., 2007; Homanics et al., 1997). Genetic linkage and
association studies in idiopathic autism cohorts have repeatedly found
signiﬁcant evidence for a susceptibility allele in GABRB3 (Buxbaum
et al., 2002; Cook et al., 1998; Martin et al., 2000; McCauley et al.,
2004; Nurmi et al., 2003b; Shao et al., 2003). Additionally, signiﬁcantly
reduced GABRB3 protein levels were commonly observed in post-
mortem brain samples from idiopathic autistic individuals (Samaco
et al., 2005) and normal biallelic GABR expression was commonly
disrupted in autistic individuals with protein expression deﬁcits
(Hogart et al., 2007). The effect of maternal 15q11.2-q13 duplications
on GABR gene expression in brain is currently unknown, however
genetic and molecular evidence suggests that GABRB3 expression
abnormalities may contribute to the autism component of these
Although located outside the critical deletion region for PWS and
AS, the nonimprinted gene CYFIP1 may contribute to the increased
severity observed in patients with larger 15q11.2-q13 deletions and
duplications. CYFIP1, the cytoplasmic FMRP interacting protein 1, was
characterized by its physical interaction with the protein product of
the Fragile X syndrome gene FMR1 (Schenck et al., 2001). Additionally
CYFIP1, also called Sra-1, interacts with the Rac1 small GTPase
(Kobayashi et al., 1998) and is proposed to play a role in bridging
cytoskeleton remodeling with translation (Schenck et al., 2003).
Similar to UBE3A, CYFIP1 has been shown to be overexpressed
in lymphoblast cell lines from 15q11.2-q13 duplication patients
(Nishimura et al., 2007). Interestingly, overexpression of CYFIP1 and
knockdown of FMR1 in a human neuronal cell line resulted in similar
effects on two downstream target genes, JAKMIP1
(Nishimura et al., 2007), suggesting that abnormalities in these
pathways may contribute to some phenotypic overlap between
15q11.2-q13 duplication syndromes and Fragile X syndrome. Further-
more, a Prader–Willi obesity and hyperphagia phenotype was recently
described in a subset of Fragile X patients with comorbid autism and
reduced transcription of nonimprinted 15q11.2-q13 gene CYFIP,
further suggesting overlap between Fragil e X and 15q11.2-q13
duplication and deletion syndromes (Nowicki et al., 2007).
Epigenetic factors regulating 15q11.2-q13
Chromosome 15q11.2-q13 parental imprinting patterns and long-
range gene expression effects are mediated by a bi-partite imprinting
control region (ICR) upstream of the large paternal transcription unit
from SNRPN through UBE3A. The PWS-ICR is hypermethylated on the
silent maternal allele and deletion of this region on the paternal
chromosome is sufﬁcient to cause PWS (Sutcliffe et al., 1994). An
AS-ICR located 35 kb upstream of the PWS-ICR is required for
establishing the maternal methylation mark at the PWS-ICR, as
deletion of this region in AS patients result in imprinting errors
(Buiting et al., 2001; Buiting et al., 1995). In addition to methylation,
other parental epigenetic marks deﬁne the PWS-ICR, including DNAse
I hypersensitivity sites and histone H3 and H4 acetylation on the
active paternal allele, and matrix attachment and histone H3K9
methylation on the silent maternal allele (Greally et al., 1999;
Rodriguez-Jato et al., 2005; Wu et al., 2006). Interestingly, methyl
CpG binding protein 2 (MeCP2) binds to the PWS-ICR and to multiple
additional intergenic sites throughout 15q11.2-q13 (Yasui et al., 2007),
potentially acting to organize long-range chromatin interactions of
the region. While MeCP2 is not required for maintaining imprinted
expression of 15q11.2-q13 genes, MeCP2 deﬁciency results in reduced
expression of both UBE3A and GABRB3 in some studies (Hogart et al.,
2007; Makedonski et al., 2005; Samaco et al., 2005). Individuals with
MECP2 mutation s have Rett syndrome, a neurod evelopmental
disorder with signiﬁcant phenotypic overlaps with AS and autism
in terms of language impairment and stereotyped mannerisms (Amir
et al., 1999; Watson et al., 2001).
Nuclear organization and homologous pairing of 15q11.2-q13
alleles in human neurons
Chromosome dosage changes to 15q11.2-q13 may also impact the
normal balance of homologous chromosome 15 interactions pre-
viously observed in both lymphocytes and neurons (LaSalle and
Lalande, 1996; Thatcher et al., 2005). Similar to X chromosome
counting mechanisms that require transient homologous X chromo-
some pairing during development for proper X chromosome
inactivation in females (Xu et al., 2006), some gene expression
patterns within 15q11.2-q13 appear to require interactions between
both parental chromosomes. Homologous pairing of maternal and
paternal 15q11.2-q13 alleles in neurons is a developmentally regulated
process and dependent on the binding of MeCP2 (Thatcher et al.,
2005). Homologous pairing of 15q11.2-q13 is deﬁcient in a subset of
Rett syndrome and autism brains and may contribute to t he
dysregulation of GABRB3 expression observed in these human brain
et al., 2005; Thatcher and LaSalle, 200 6). These
observations have lead to the hypothesis that 15q11.2-q13 homo-
logous pairing may be required for optimal biallelic expression of
GABRB3. Examination of a brain sample from a mosaic complex der
(15) patient by FISH has revealed that der(15) alleles can pair with the
normal parental chromosome 15s (Wang et al., 2008), suggesting that
additional copies of this region can disrupt the normal balance of
homologous pairing of 15q11.2-q13 alleles in the brain and potentially
impact GABRB3 expression in a manner not predicted by gene dosage.
7A. Hogart et al. / Neurobiology of Disease xxx (2008) xxx–xxx
ARTICLE IN PRESS
Although maternal duplications of 15q11.2-q13 are the most
common cytogenetic ca use of autism, not all individuals wit h
dupl ications have classic autism, so understan ding the mole-
cular basis of the clinical heterogeneity is imperative. The clinical
heterogeneity among individuals with similar duplications suggests
that genetic or epigenetic modiﬁers inﬂuence gene expression of
15q11.2-q13 genes o r the downstream targets of these genes.
Generation of a mouse model with excess maternal dosage for the
syntenic region to 15q11.2-q13 (7qB4) is critical to begin to elucidate
how the duplication affects gene expression in the developing
mammalian brain. While mice provide controlled models for human
disorders, differences in genetic backgrounds and biology between
humans and mice may prove challenging in creating a good model for a
variable human disorder (as proven by the difﬁculties in creating an
appropriate mouse model for PWS). Complementary molecular and
pathological studies of human brain samples are also necessary to
critically evaluate how extra 15q11.2-q13 dosage affects neurological
function. Although the maternally expressed imprinted gene UBE3A
may be predicted to drive the pathogenesis of 15q11.2-q13 duplica-
tions, the complex regulation and trans effects observed in this locus
suggest that any level of abnormal parental dosage may impair normal
The authors are supported by grants from the National Institutes of
Health [NIH F31 MH078377 (AH), NIH R01 HD48799 (JML), NIH P3P01
HD35470 (NCS), NIH R01 HD37874 (NCS), P20-RR020173 (NCS)], and
Nemours (NCS and DW). We are indebted to the Isodicen tri c
Exchange, Advocacy and Support Group and families with idic(15)
for their participation in the ongoing research into the investigation of
the phenotype of patients with idic(15) and interstitial duplication 15
chromosomes. The authors also thank Suzanne Cassidy for providing
detailed information on an unpublished case interstitial triplication
chromosome 15 and the relationship with PWS and ASD.
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