Major influence of repetitive elements on disease-associated copy number variants (CNVs)
Cardoso et al. Human Genomics
Major influence of repetitive elements on disease-associated copy number variants (CNVs)
Ana R. Cardoso 0 1 2 3 4
Manuela Oliveira 0 1 2 3 4
Antonio Amorim 0 1 2 3 4
Luisa Azevedo 0 1 2 3 4
0 IPATIMUP-Institute of Molecular Pathology and Immunology, University of Porto , Rua Júlio Amaral de Carvalho 45, 4200-135 Porto , Portugal
1 Instituto de Investigação e Inovação em Saúde, Universidade do Porto , Rua Alfredo Allen 208, 4200-135 Porto , Portugal
2 Department of Biology, Faculty of Sciences, University of Porto , Rua do Campo Alegre S/N, 4169-007 Porto , Portugal
3 IPATIMUP-Institute of Molecular Pathology and Immunology, University of Porto , Rua Júlio Amaral de Carvalho 45, 4200-135 Porto , Portugal
4 Instituto de Investigação e Inovação em Saúde, Universidade do Porto , Rua Alfredo Allen 208, 4200-135 Porto , Portugal
Copy number variants (CNVs) are important contributors to the human pathogenic genetic diversity as demonstrated by a number of cases reported in the literature. The high homology between repetitive elements may guide genomic stability which will give rise to CNVs either by non-allelic homologous recombination (NAHR) or non-homologous end joining (NHEJ). Here, we present a short guide based on previously documented cases of disease-associated CNVs in order to provide a general view on the impact of repeated elements on the stability of the genomic sequence and consequently in the origin of the human pathogenic variome.
Copy number variants (CNVs); Genetic diseases; Genomic structural variation; Low copy repeats; Retrotransposons; LINE; SINE; Non-allelic homologous recombination (NAHR)
Copy number variants (CNVs) are structural genomic
markers (insertions or deletions) ranging in size from
1 kb to several megabytes for each copy. They are
categorized as copy number polymorphisms (CNPs) when
multiple allelic states exist in the population or as rare
copy number variants when they are found to be
associated with genetic diseases (pathogenic copy number
variants) [1, 2]. The origin of each repeated element of
the CNV is influenced by the local genomic architecture
which includes the presence of repetitive sequences
within or flanking the repeated segment [3–7]. These
repeated sequences drive non-allelic homologous
recombination (NAHR) events which result in recurrent
insertions and deletions with similar sequence sizes and
clustered breakpoints [3, 6, 8] or non-homologous end
joining (NHEJ) events that result in non-recurrent
rearrangements that vary in terms of their size and
breakpoint location [3, 6, 9]. Although several studies have
been demonstrating the contribution of structural
variants to the genome architecture, few have specifically
focused the influence of repeated sequences at
breakpoint locations. With the aim to draw attention to these
unstable regions and to establish their role in CNVs, we
collated a number of cases of CNV-associated disorders
proven to have been generated by low and high copy
number repeats which may have influenced the degree
of stability of the genomic sequence.
Low copy repeats and their influence on
pathogenic CNV formation
Low copy repeats (LCRs) are homologous sequences
of ≥1 kb in length which are found in many copies
throughout the genome since they are generated by
duplication events [3, 10]. Large LCRs (>10 kb) with
high sequence homology promote non-allelic
homologous recombination (NAHR) [3–6, 10–12] and the
misalignment of directly oriented sister chromatids
carrying the LCR may promoted NAHR thereby
generating both duplications and deletions [4, 5] which in
turn give rise to copy number variation. A schematic
representation of this process is shown in Fig. 1.
Certain properties of the LCRs such as homology
length, sequence similarity, and distance, serve to
influence the frequency of NAHR events [3, 6, 12] (Fig. 1). As
recently reviewed by Carvalho and Lupski , the NAHR
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Fig. 1 Optimal LCRs features for the occurrence of NAHR events that result in CNV formation. Distinct LCR pairs with counter features such as
homology, size, and inter-LCR distance influence NAHR rate and lead to the formation of common recurrent (a) or rare recurrent (b) copy number
variants. Adapted from [3, 6, 12]
rate varies according to the length of the LCR sequence,
the distance between distinct LCR sequences and the
DNA sequence. The NAHR rate is, therefore, positively
correlated with the LCR length but is inversely
proportional to the distance between distinct LCRs [3, 9]. Since
there is a high homology between distinct LCR sequences
proximal to copy number variation regions; there is also
an increased predisposition to NAHR events in these
genomic regions [3, 4, 6, 9, 12].
A considerable number of disease-associated CNVs
generated by LCRs have been documented and reviewed
in previous works (e.g. [3, 6]), but for the purposes of
this paper, we have only collated cases for which the
specific repetitive element was found at the breakpoints of
the structural variant and not those for which the
causality of the repeats elements was only suggested. The
resulting set is presented in Table 1. For example, a
complex array of LCRs spanning a 4-Mb region around
the X-linked MECP2 gene was associated with unique
duplications ranging in size from 200 kb to 2.2 Mb in
developmentally delayed males . Duplications and
deletions affecting the PLP1 gene causing
PelizaeusMerzbacher disease (OMIM #312080) are also
associated with a specific LCR (LCR-PMD A/B pair) within a
3-Mb region flanking the gene in which a multitude of
LCRs are located . LCRs are also frequent at the
2q11-q21.1 locus , where recurrent deletions of the
NPHP1 gene (2q13) have been associated with
nephronophthisis 1 (OMIM #256100). A 0.3-Mb copy number
gain was detected in three X-linked intellectual disability
(XLID) families and one sporadic patient . The region
overlapped the GDI1 gene, an important XLID-associated
Table 1 Repetitive elements detected at the breakpoints of CNVs associated with clinical phenotypes
Neurofibromatosis type I
Mental retardation, X-linked 41 (MRX41) GDI1
Angelman and Prader-Willi syndromes
15q13.1 microdeletion syndrome
Repetitive element involved Ref.
Several LCR-MECP2s pairs [3, 6, 13, 44–46]
28 dosage-sensitive genes Dup/Tripe/Del 7q11.23
15q11-q13 END-repeats (LCRs)
Several LCR-MECP2 pairs
8 specific LCR22 repeats
gene highly expressed in the brain. The aberration was
located in Xq28, a locus that includes other intellectual
disability genes and that is frequently associated with
recombination events caused by proximal LCRs (e.g., LCR
K1/L2). The Angelman syndrome (AS) (OMIM #105830)
and Prader-Willi syndrome (PWS) (OMIM #176270) are
caused by recurrent 4-Mb deletions at the 15q11-q13
locus. The deleted region is flanked by LCRs  and
accounts for 70 % of cases of AS and 70–75 % of cases of
PWS . The Smith-Magenis syndrome (SMS) (OMIM
#182290) results from recurrent deletions of 3.7 Mb at
17p11.2 which account for more than 70 % of cases; about
25 % of affected individuals harbor deletions ranging from
1.5–9 Mb [6, 17]. The deletions are flanked by 200-kb
highly homologous LCRs that play a role in generating
meiotic NAHR events . These deletions encompass
the RAI1 gene, which is critical in organ and neuronal
development—patients with larger deletions manifest a
more severe phenotype when the dosage-sensitive gene
PMP22 is deleted .
Retrotransposons (high copy repeats) and their
influence on pathogenic CNVs
Interspersed repeats are the most common type of high
copy repeats, covering about 44 % of the human genome
. Retrotransposons account for the majority of
transposable elements [5, 7, 19]. These are mobile elements
that through reverse transcription have the ability to
integrate into different regions [7, 19]. Long interspersed
nuclear elements (LINEs), short interspersed nuclear
elements (SINEs), and retrovirus-like elements (LTR
transposons) are the three major categories of mammalian
retrotransposons (Table 2).
Among LINEs, L1 is the most abundant element,
typically of 6–8 kb in length, with the ability to increase
genomic instability through NAHR events . It is known that
about 83 % of the human genome is prone to LINE-LINE
recombination events that contribute to genomic
instability and can give rise to unbalanced structural variants .
Alu elements are the most common SINEs and have
been associated with NAHR events that lead to
pathogenic duplications and deletions [3, 4, 21, 22]. Table 3
presents examples of high copy repeats that have been
detected at the breakpoints of disease-associated CNVs.
Borun and colleagues  reported the presence of
CNV breakpoints within Alu elements in the STK11
gene which lead to the Peutz-Jeghers syndrome (OMIM
#175200), where CNVs account for 30 % of cases. The
17p13.3 locus is enriched in copy number variations
associated with genomic disorders, such as the
MillerDieker syndrome (17p13.3 deletion syndrome) (OMIM
#247200) and its reciprocal 17p13.3 duplication
syndrome (OMIM #613215) . The breakpoints of the
reported CNVs at this locus are highly enriched in Alu
elements, which mediate these junctions through an
Alu-Alu mechanism. About 70 % of CNVs found in the
SPAST gene have been associated with Alu
recombination events . Local Alu-rich architecture
predisposes to the formation of pathogenic structural
rearrangements associated with spastic paraplegia
(OMIM #182601). An extra copy of the LMNB1 gene at
the 5q23 locus has been previously associated with
autosomal dominant adult-onset demyelinating
leukodystrophy (ADLD) (OMIM #169500). The analysis of twenty
ADLD-affected families revealed sixteen duplications
ranging from 128 to 475 kb in size, all of them spanning
the LMNB1 gene . The centromeric region of the
critical gene is enriched with SINE elements, particularly
Alus. Alu-mediated recombination events were also
found to be linked to pathogenic deletions at the OTC
gene , a urea cycle gene for which a significant
number of structural variants are known . NAHR events
between Alu repeats are also strongly correlated with
the birth of structural rearrangements at the Alu-rich
BRCA1 locus  which is associated with breast cancer.
Duplications (220 to 394 kb) and a triplication (1.61 to
2.04 Mb) of the SNCA gene located at 4q21 locus have
been implicated in autosomal dominant Parkinson’s
disease (PD1 and PD4) (OMIM #168601, #605543). The
phenotypic severity is consistent with a gene dosage
effect . Regarding recessive PD (OMIM #600116), about
one third of pathogenic variants associated with the
PRKN gene are CNVs occurring between exon 2 and
exon 5, which may therefore be considered to be a
Table 2 Main characteristics of the most abundant retrotransposons [4, 5, 7, 19]
Short interspersed nuclear repeats (SINEs)
Alu is the most abundant class
Dependent on LINEs transposable
Mobile polymerase III promoter
100–400 bp in length
Long terminal repeat (LTR)
Endogenous retroviruses (ERV)
Spastic paraplegia 4
Autosomal dominant adult-onset demyelinating LMNB1
Mental retardation, X-linked 60 (MRX60)
DiGeorge syndrome/velo-cardio facial syndrome COMT, TBX1
Charcot-Marie-Tooth type 1A
28 dosage-sensitive genes Dup/Del
Repetitive elements involved Ref.
Several AluY/AluY pairs 
17q21.31 AluSx/AluSc pair
LIPA3 LINE repeats
HERV15 A/B proviruses
Unclassified Alu/Alu pair
AluS subfamily elements
Table 3 High copy repeats detected at the breakpoints of CNVs associated with clinical phenotypes
recombination hotspot [30, 31]. Ross and colleagues 
reported the presence of Alu and LINE1 elements at the
SNCA locus that may contribute to the genomic
instability at this locus.
Human endogenous retroviruses (HERVs) represent
about 4.9 % of the human genome . Sequences with
about 95 % sequence similarity were previously
associated with NAHR events and recurrent CNVs, some of
which with pathogenic implications [3, 33]. For example,
the occurrence of NAHR between a particular set of
HERV elements flanking the male fertility AZFa locus in
the Y chromosome is strongly associated with pathogenic
deletions associated with male infertility (OMIM #400042,
#415000) [4, 34].
Pathogenic copy number variants associated with
both LCRs and retrotransposons
The breakpoints of some disease-associated CNVs have
been reported to be caused by more than one type of
repetitive elements which indicates that the same
phenotype involves both low copy and high copy repeats that
affect the stability of a target gene. Bergmann and
colleagues  conducted a family study in which five
brothers shared the same phenotypic pattern that
included intellectual disability. The analysis of the OPHN1
locus (Xq12) revealed the presence of a 17.6-kb intronic
deletion and the breakpoints spanning the deletion
revealed two highly homologous Alu repeats and
additional repetitive sequences (interspersed and simple
A recurrent deletion of 1.6 to 1.8 Mb (>95 % of the
patients) at the 7q11.23 locus causes the Williams-Beuren
syndrome (OMIM #194050) . Genes within this
region are dosage-sensitive and the recurrently deleted
region encompasses a total of 28 genes. This locus is
characterized by highly homologous flanking LCRs that
contribute to NAHR events . Antonell and colleagues
 reported the presence of Alu elements at the
junctions of large duplicated blocks in 7q11.23 suggesting
the influence of these retrotransposons in the generation
of large LCRs.
Heterozygous duplication and reciprocal deletions of a
1.4–1.5-Mb segment at the 17p12 locus have been
previously linked with the Charcot-Marie-Tooth type 1A
syndrome (CMT1A) (OMIM #118220). About 70 % of
CMT1A patients have a recurrent duplication of the
dosage-sensitive PMP22 locus and the NAHR event that
gave rise to this copy number variation was mediated by
LCRs [3, 6, 37, 38]. A study by Zhang and colleagues
 revealed the presence of SINEs (Alu elements) and
LINEs (L1 and L2) as well as LCRs within the
breakpoints of rare non-recurrent deletions and duplications
at the CMT1A locus.
About 96 % of the DiGeorge syndrome (DGS) (OMIM
#188400)- and velo-cardio-facial syndrome (VCFS)
(OMIM #192430)-affected patients harbor a 1.5–3 Mb
deletion at the 22q11.2 locus that includes 24 to 30
genes . The breakpoints of the common recurrent
deletions at this locus are associated with LCRs  and
one Alu sequence . Both the deletions and
duplications at this locus are generated by NAHR events
between the repeated regions flanking the CNV,
specifically the low copy repeat known as LCR22 .
Furthermore, 20–25 % of individuals who harbor this deletion
also show signs of schizophrenia, mood disorders, and
other behavioral alterations .
Although the majority of genetic diseases are caused by
non-structural variants (e.g. [42, 43], an increasing
number of causative mutations have been associated with
CNVs and these cases were the focus of this short
review. Low copy repeats and retrotransposons are the
major contributors to CNV formation. Recurrent CNVs
are mainly directed by NAHR events that occur between
highly homologous LCR sequences. In terms of
nonrecurrent CNVs, NHEJ (among other molecular
mechanisms ) generally occurs between sequences with a
degree of homology lower than that observed between
distinct LCRs. The diversity of breakpoint junctions of
non-recurrent variants renders the establishment of
phenotype-genotype relationships less reliable because
the sequence that is deleted or duplicated in each patient
is different and the affected region may also involve
other genes. This review focused on disease-associated
CNVs in order to show that although numerous cases of
instability driven by repeated sequences around the
affected locus (or loci) have been documented, we are still
far from understanding all the phenotypic complexities
associated with these unbalanced variants, mainly
because the number of reported cases is still too small to
draw general conclusions. Finally, it is important to
mention that collated data, such as those presented in
this paper, pertaining to the pathogenic structural
variome are expected to drive future studies with the aim of
establishing a map of unstable genomic hotspots which
promises to be useful in the context of clinical genetic
testing where the determination of the molecular basis
of Mendelian and complex diseases (e.g., cancer) is of
CNV: Copy number variant; LCR: Low copy repeat; CNP: Copy number
polymorphism; LINE: Long interspersed nuclear repeat; SINE: Short
interspersed nuclear repeat; LTR: Long terminal repeat; NAHR: Non-allelic
homologous recombination; NHEJ: Non-homologous end joining; XLID:
Xlinked intellectual disability
IPATIMUP integrates the i3S Research Unit, which is partially supported by
FCT, the Portuguese Foundation for Science and Technology. This work is
funded by FEDER funds through the Operational Programme for
Competitiveness Factors - COMPETE and National Funds through
the FCT-Foundation for Science and Technology, under the projects
M. Oliveira (SFRH/BPD/66071/2009) was supported by FCT fellowships
funded by POPH-QREN - Promotion of Scientific Employment, the European
Social Fund, and National Funds of the Ministry of Education and Science.
ARC performed literature search. ARC and LA drafted the manuscript.
MO and AA discussed the data and performed critical revisions to the
manuscript. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
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