American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 145C:346– 356 (2007)

A R T I C L E

Monosomy 1p36 Deletion Syndrome

MARZENA GAJECKA, KATHERINE L. MACKAY, AND LISA G. SHAFFER*

Monosomy 1p36 results from a heterozygous deletion of the most distal chromosomal band on the short arm of
chromosome 1. Occurring in
1 in 5,000 live births, monosomy 1p36 is the most common terminal deletion
observed in humans. Monosomy 1p36 is associated with mental retardation, developmental delay, hearing
impairment, seizures, growth impairment, hypotonia, and heart defects. The syndrome is also characterized by
several distinct dysmorphic features, including large anterior fontanels, microcephaly, brachycephaly, deep-set
eyes, flat nose and nasal bridge, and pointed chin. Several genes have been proposed as causative for individual
features of the phenotype. In addition, based upon molecular characterization of subjects with monosomy 1p36,
several mechanisms for the generation and stabilization of terminal deletions have been proposed.
ß 2007 Wiley-Liss, Inc.

KEY WORDS: monosomy; 1p36; deletion; telomere

How to cite this article: Gajecka M, Mackay KL, Shaffer LG. 2007. Monosomy 1p36 deletion syndrome.
Am J Med Genet Part C Semin Med Genet 145C:346–356.

HISTORICAL OVERVIEW
Yunis et al. [1981] published a case
report of a 4-year-old female with
severe mental retardation and congenital
anomalies including wide fontanels,
generalized hypotonia and a grade III/
IV systolic murmur. Although banding
analysis showed her karyotype to be a
balanced 45,XX,ter rea(1;21)(p36;p13),
the authors suggested that a submicro-
scopic deletion of 1p might account for
the patient’s clinical features. The first
true deletion of chromosome 1p36
Marzena Gajecka, Ph.D., is an Assistant
Research Professor in the Department
of Health Research and Education at
Washington State University in Spokane.
Her research focuses on the mechanisms
involved in chromosomal rearrangements.
Katherine L. Mackay is a Master’s degree
student in Health Policy and Administration
at Washington State University in Spokane.
Lisa G. Shaffer is a co-founder and
scientific director at Signature Genomic
Laboratories, LLC, in Spokane, WA. She is
also a professor at Washington State Uni-
versity. Dr. Shaffer received her PhD from the
Medical College of Virginia.
*Correspondence to: Lisa G. Shaffer,
Ph.D., Health Research and Education Cen-
ter, Washington State University, Box 1495,
Spokane, WA 99210-1495.
E-mail: lshaffer@wsu.edu
DOI 10.1002/ajmg.c.30154
(excluding those reported only in
abstract form) was reported by Biegel
et al. [1993] in a child with neuro-
blastoma and congenital anomalies
including hypertelorism, a depressed
nasal bridge, high-arched palate and
neurological manifestations including
head lag and hypotonia. Although some
of the patient’s features were consistent
with those of the patient described by
Yunis et al. [1981], the authors were not
able to define a specific phenotype
associated with deletion of 1p36.
In a review of the first 13 patients
reported with small terminal dele-
tions involving chromosome 1p36.22,
Keppler-Noreuil et al. [1995] proposed
two distinct phenotypes differentiated
by growth failure versus macrosomia.
The authors speculated that the different
subgroups might be a consequence of
parental origin or differences in dele-
tion size. However, this cohort was not
confined to patients with pure 1p36
deletions; most of the patients had
double segmental imbalances owing to
unbalanced translocations. Thus, the
clinical characteristics resulting from
deletion of 1p36 could not be distin-
guished from those caused by imbalance
of the other chromosome.
By examining 13 patients with iso-
lated deletions of 1p36 and excluding
patients with unbalanced translocations,
Shapira et al. [1997] delineated the
phenotype of the chromosome 1p36
deletion syndrome. Clinical examina-
tion of the patients revealed that the most
common features of this syndrome were
mental retardation, large anterior fonta-
nel, motor delay/hypotonia, vision and
hearing problems, seizures, and growth
delay. Patients also had characteristic
facial features including flat nasal bridge,
low-set ears with thickened helices, and
deep-set eyes. The authors also con-
cluded that, although the facial features
proposed by Keppler-Noreuil et al.
[1995] as representative of two distinct
phenotypes did, in fact, each appear in a
proportion of the patients, these facial
features did not separate the patients
into two discrete groups. In addi-
tion, fluorescence in situ hybridization
(FISH) and DNA polymorphism analy-
sis showed that the deletion sizes among
patients were variable with a com-
mon minimum region of overlap and
that the variability of deletion sizes
might explain the phenotypic variability
among patients with 1p36 deletions.
Furthermore, based upon population
studies of patients ascertained with
deletion of 1p36 among live births
in the same geographical area, the
authors suggested that the incidence of

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ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c
monosomy 1p36 appeared to be 1/
10,000 [Shapira et al., 1997].
In a study of the largest cohort of
subjects with monosomy 1p36 ascer-
tained to date, Heilstedt et al. [2003b]
characterized the deletion sizes in 61
subjects using a contig of overlapping
bacterial artificial chromosome (BAC)
clones mapping to the most distal
10.5 Mb of 1p36. The authors found
pure terminal deletions, interstitial de-
letions, derivative chromosomes, and
more complex rearrangements, with
no common breakpoint. The authors
In a study of the largest cohort
of subjects with monosomy
1p36 ascertained to date,
characterized the deletion sizes
in 61 subjects using a contig of
overlapping BAC clones
mapping to the most distal
10.5 Mb of 1p36. The authors
found pure terminal deletions,
interstitial deletions, derivative
chromosomes, and more
complex rearrangements, with
no common breakpoint.
also suggested that, because half of their
patients had had at least one chromo-
some analysis interpreted as normal
prior to ascertainment, it was likely that
monosomy 1p36 was twice as prevalent
in the general population as previously
estimated [Heilstedt et al., 2003a]. Their
estimate of the incidence of monosomy
1p36 as 1 in 5,000 live births makes it
the most common terminal deletion
observed in humans.
EPIDEMIOLOGY
Rearrangements of 1p36 resulting in
deletion are observed in 1 in 5,000
live births [Shaffer and Lupski, 2000;
Heilstedt et al., 2003a]. Deletions occur
equally in both males and females and
across all ethnicities. Of the 95% of
deletions that are de novo, 60% occur
on the maternally derived chromosome
and 40% occur on the paternally derived
chromosome [Heilstedt et al., 2003b]. In
a summary of all published studies using
subtelomeric FISH probes, monosomy
1p36 was the most commonly identified
terminal deletion among the patients
studied [Heilstedt et al., 2003b].
In the past, unfamiliarity with the
clinical phenotype of monosomy 1p36
may have contributed to a low ascertain-
ment rate of patients [Zenker et al.,
2002]. Although the majority of
reported cases of monosomy 1p36 have
been identified through cytogenetic
analyses, the deletion is difficult to
visualize by routine chromosome
analysis at the 400- to 550-band reso-
lution. Often, it is not possible to detect
these deletions with banded karyotypes
[Riegel et al., 1999; Shaffer, 2005].
Because subtelomere FISH analysis has
increasingly been used in addition to
routine cytogenetic analysis in children
with mental retardation [Ravnan et al.,
2006], many more terminal deletions of
1p36 are currently being identified.
However, in cases with interstitial dele-
tions and complex rearrangements, a
targeted FISH approach may be neces-
sary [Heilstedt et al., 2003b]. This is
because some subtelomeric probes do
not cover regions proximal to the
subtelomere which are deleted in inter-
stitial deletion cases. For these cases, it is
helpful to perform metaphase FISH with
additional probes corresponding to the
proximal sequence. In complex rear-
rangements, interphase FISH may help
to delineate the complexity of the
rearrangement [Gajecka et al., 2005].
However, for most cases, array-based
comparative genomic hybridization
(CGH) can be used to define the type
of rearrangement and the extent of the
imbalances (Fig. 1) [Yu et al., 2003].
Array CGH is a diagnostic tool
that merges molecular diagnostics and
traditional chromosome analysis [Bejjani
and Shaffer, 2006; Shaffer and Bejjani,
2006]. Array CGH detects abnormal-
ities by comparing DNA content from
two differently labeled genomes [Bejjani
and Shaffer, 2006]. It has the ability to
detect any genomic imbalance includ-
ing deletions, duplications, aneuploidies,
347
and amplifications [reviewed in Shaffer
and Bejjani, 2006]. The primary advant-
age of array CGH, compared with
FISH, is that the array is capable of
simultaneously detecting DNA copy
changes at multiple loci over the whole
genome [Bejjani and Shaffer, 2006]. In
essence, array CGH is a concurrent
FISH experiment over hundreds or
thousands of loci [Bejjani and Shaffer,
2006].
Recently, 1p36 deletions were
identified in a large number of patients
through the screening of individuals
with mental retardation and develop-
mental disabilities by array CGH
[Shaffer et al., 2006]. In this study,
1,500 cases were screened using a micro-
array designed specifically to identify
chromosome abnormalities. In those
1,500 cases, 84 were chromosomally
abnormal and 8 of these (10%) were
rearrangements of 1p36. More recently,
Recently, 1p36 deletions were
identified in a large number of
patients through the screening
of individuals with mental
retardation and developmental
disabilities by array CGH. In
this study, 1,500 cases were
screened using a microarray
designed specifically to identify
chromosome abnormalities.
In those 1,500 cases, 84 were
chromosomally abnormal
and 8 of these (10%) were
rearrangements of 1p36.
a study of 8,789 patients studied by array
CGH showed that 1p36 abnormalities
are one of the most common, with 45 of
604 abnormal cases involving this region
[Shaffer et al., this issue].
CLINICAL FEATURES
Monosomy 1p36 is associated with
mental retardation, developmental delay,
348 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c ARTICLE

Common craniofacial features include

microcephaly, brachycephaly, deep-set
eyes, flat nose and nasal bridge, and
pointed chin [Shapira et al., 1997;
Slavotinek et al., 1999; Battaglia, 2005].
Among our subjects, for which the
specific features were examined, we
found that large anterior fontanel,
microcephaly, brachycephaly, thickened
ear helices, deep-set eyes, midface hypo-
plasia, flat nasal bridge, pointed chin, and
clinodactyly occurred in over 50% of
subjects.

Neurologic
Mental retardation of variable degree,
mostly moderate to severe, is present in
all individuals with monosomy 1p36
[Shapira et al., 1997]. Language skills are
commonly delayed in patients with
monosomy 1p36. Although expressive

All subjects have mental

retardation of varying degrees,
mostly moderate to severe, as
assessed with a number
of neuropsychiatric tests
depending on the age of the
Figure 1. Array CGH plots for chromosome 1 from the SignatureChip1 micro-
array analysis showing chromosome abnormalities found in patients with 1p36 deletions. subject. Language skills are
Array CGH data for all of the chromosome 1 BAC clones represented on the microarray
are displayed with the most distal p-arm clone on the left and the most distal q-arm clone commonly delayed in patients
on the right. The blue line is a plot of the data from the first array CGH experiment
(reference Cy5/patient Cy3). The pink line is a plot of the data from the second array with monosomy 1p36.
CGH experiment in which the dyes have been reversed (patient Cy5/reference Cy3).
A: A normal array CGH plot for chromosome 1. B: Chromosome 1 plot from a case
showing a terminal deletion of 1p36 that is
3.4 Mb in size. C: Chromosome 1 plot from language skills are affected in most
a case showing an interstitial deletion of 1p36. The deletion begins about 1.9 Mb from the
telomere and extends approximately 6.3 Mb toward the centromere. [Color figure can be individuals, patients with small deletions
viewed in the online issue, which is available at www.interscience.wiley.com.] and relatively complex speech abilities
have been reported [Battaglia, 2005].
Speech delays were reported in 98% of
our subjects. In addition, 79% of subjects
had seizures; many of these patients were
reported previously and details of their
hearing impairment, seizures, growth physician questionnaire, we have fur- seizure history given [Heilstedt et al.,
impairment, hypotonia, heart defects, ther characterized this syndrome and 2001]. Over 50% of subjects showed
and distinct dysmorphic features (Fig. 2). summarize the clinical findings in hypotonia, feeding difficulties, and oro-
Our laboratory has ascertained 134 Table I. pharyngeal dysphasia. Finally, 55% of
subjects with monosomy 1p36. The subjects had self-abusive behaviors.
clinical characterization of the first Abnormalities found by MRI included
Dysmorphic Features
60 subjects has been previously pub- polymicrogyria, leukoencephalopathy,
lished [Heilstedt et al., 2003b]. Through Monosomy 1p36 is recognized by generalized atrophy, and prominent
the review of medical records and a distinct facial characteristics (Fig. 2). ventricles (Table I).
ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c 349

an abnormality. Cardiomyopathy was

found in 18 subjects, and 44 had a
structural heart defect. Table I lists the

Of the 134 subjects, 59 had

reported cardiac evaluations
that revealed an abnormality.
Cardiomyopathy was found in
18 subjects, and 44 had a
structural heart defect.

type of defect and their relative

occurrences.

Other Features
Features reported in only one published
case include redundant skin on the nape
of the neck [Wang and Chen, 2004],
intestinal malrotation and annular pan-
creas [Minami et al., 2005], congenital
spinal stenosis [Reish et al., 1995],
Figure 2. Facial features of four subjects with deletions of 1p36. Note the mid-face telangiectatic skin lesion and hyper-
hypoplasia, flat nasal bridge, pointed chin, hypertelorism and deep-set eyes. Two different pigmented macules [Keppler-Noreuil
female subjects are shown at age 13 years, 7 months (A) and age 6 years, 5 months (B). The et al., 1995], and polydactyly [Keppler-
same male subject is shown at ages 9 (C) and 15 (D). [Color figure can be viewed in the
online issue, which is available at www.interscience.wiley.com.] Noreuil et al., 1995]. We have found
a substantial number of cases with
gastrointestinal complaints including
constipation, reflux, and general GI
discomfort (Table I).

Auditory and Ophthalmologic Endocrinologic Correlation of the Phenotype

Systems
Complete auditory evaluations, which
included testing at high frequencies
(6–8 kHz), were obtained on 52 sub-
jects. Testing was done by auditory
brainstem evoked response (ABER)
or sound field evaluation. Of these
52 subjects, 77% showed hearing defi-
cits, either conductive, sensorineural, or
both.
Strabismus was the most common
ophthalmologic finding reported in
our subjects with hypermetropia and
myopia occurring in about 40% of
subjects examined. Visual inattentive-
ness, defined as absence of attentive
visual behavior with fixation and fol-
lowing movements, also occurred in
about 40% of subjects.
Two of six individuals examined in our
original cohort of 60 subjects had hypo-
thyroidism and were on thyroid sup-
plementation [Heilstedt et al., 2003b].
Baseline thyroid studies on the remain-
ing subjects showed that four others
had elevated TSH (thyroid stimulating
hormone) levels with corresponding
low T4 levels. Although this in-
formation was not obtained in subjects
61–134, perhaps as many as 20%
of subjects have hypothyroidism, and
thyroid function studies should be a part
of the clinical workup of patients with
monosomy 1p36.
Cardiovascular
Of the 134 subjects, 59 had report-
ed cardiac evaluations that revealed
With Deletion Sizes
It was originally believed that there were
two separate phenotypes, both charac-
teristic of a 1p36 deletion and sharing
some dysmorphic features [Keppler-
Noreuil et al., 1995]. The first was
characterized by impairment of growth
and heart failure, the second associated
with obesity and physical characteristics
similar to patients with Prader-Willi
syndrome. Although a single character-
istic phenotype of monosomy 1p36 has
since been established, it may be possible
that different phenotypic subgroups
exist relating to the size of the deletion
and location of the deletion breakpoint
[Keppler-Noreuil et al., 1995]. For
example, a correlation between the
severity of the neurological deficit and
350 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c ARTICLE

TABLE I. Clinical Features Found in Subjects With 1p36 Terminal or Interstitial Deletions

Affected
Feature (total subjects examined) Percentage
Dysmorphic features
Large anterior fontanelle 34 (46) 74
Microcephaly 28 (46) 61
Brachycephaly 25 (46) 54
Low hairline 20 (42) 48
Small ears 21 (44) 48
Low-set ears 23 (47) 49
Ear asymmetry 18 (45) 40
Thickened ear helices 26 (45) 58
Synophrys 6 (28) 21
Deep-set eyes 36 (49) 73
Hypertelorism 15 (40) 38
Small palpebral fissures 10 (37) 27
Upslanting palpebral fissures 12 (44) 27
Downslanting palpebral fissures 11 (43) 26
Midface hypoplasia 21 (41) 51
Flat nasal bridge 40 (54) 74
Pointed chin 29 (46) 63
Clinodactyly 27 (45) 60
Neurological
Mental retardation 39 (41) 95
Developmental delay 67 (67) 100
Speech delay 56 (57) 98
Seizures 44 (56) 79
Epileptic encephalopathy 10 (32) 31
Hypotonia 59 (64) 92
Feeding difficulties 36 (47) 77
Oropharyngeal dysphasia 17 (35) 49
Self-abusive behavior 21 (38) 55
Opthalmologic and audiologic
Hypermetropia 13 (32) 41
Myopia 12 (30) 40
Strabismus 28 (42) 67
Visual inattentiveness 12 (27) 44
Hearing problems 40 (52) 77
Conductive hearing loss 16 (35) 46
Sensorineural hearing loss 19 (33) 58
Gastrointestinal
Constipation 28 (43) 65
Reflux 23 (41) 56
Ulcer 1 (26) 4
Hiatal hernia 2 (26) 8
Discomfort 4 (23) 17
Affected Percentage of subjects with a particular
Feature (total subjects with heart defects) heart defect

Cardiovascular
Cardiomyopathy 18 (59) 31
Structural congenital heart defects 44 (59) 75
(Continued )
ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c
Feature
Patent foramen ovale
Patent ductus arteriosus
Ventricular septal defects
Atrial septal defect
Ebstein anomaly
Bicommissural aortic valve
Feature
MRI abnormalities
Polymicrogyria
Leukoencephalopathy
Generalized atrophy
Prominent ventricles
the size of the terminal deletion has been
previously proposed [Kurosawa et al.,
2005].
In an attempt to demonstrate that
monosomy 1p36 is consistent with a
contiguous gene deletion syndrome, we
performed an analysis of the relationship
between the deletion size and the
number of observed clinical features.
In an attempt to demonstrate
that monosomy 1p36 is
consistent with a contiguous
gene deletion syndrome, we
performed an analysis of the
relationship between the
deletion size and the number
of observed clinical features.
Eight commonly observed clinical fea-
tures were chosen: large anterior fonta-
nel, hearing problems, structural heart
defects, seizures, hypotonia, feeding
difficulties, speech delay, and strabismus.
Mental retardation and developmental
delay were excluded because they are
present in nearly 100% of cases. We
found no correlation between the dele-
TABLE I. (Continued)
Affected
(total subjects with heart defects)
14 (59)
16 (59)
17 (59)
5 (59)
2 (59)
2 (59)
Affected
(total subjects who had an MRI)
10 (50)
14 (50)
9 (50)
13 (50)
tion size and the number of observed
clinical features. Even subjects with
We found no correlation
between the deletion size
and the number of observed
clinical features.
relatively small deletions (<3 Mb) can
present with most of the features asso-
ciated with monosomy 1p36 (Fig. 3).
This finding may support that most
genes associated with the phenotype of
monosomy 1p36 are at the distal end of
the chromosome that is deleted for most
patients [Zenker et al., 2002]. However,
for certain features (e.g., hearing loss
and seizures, Shaffer, LG, unpublished
work), a larger deletion seems to cause
more severe presentations, suggesting
that the deletion of additional genes
located more proximal to the telomere
may be causative or modifiers of these
features. In contrast, Redon et al. [2005]
suggested that the phenotype associated
with monosomy 1p36 may be caused by
a position effect rather than a contiguous
gene deletion syndrome because they
reported two cases that exhibited very
351
Percentage of subjects with a
particular heart defect
24
27
29
8
3
3
Percentage of subjects showing a
particular feature after MRI
20
28
18
26
similar clinical findings but had non-
overlapping deletions.
CANDIDATE GENES
FOR FEATURES OF
MONOSOMY 1P36
The distal end of the short arm of
chromosome 1 is very gene rich. Thus,
the number of genes found in this region
make identification of specific genes
involved in particular features difficult.
Even so, a few genes have been impli-
cated as potential candidates for some
of the features in patients with 1p36
deletion.
SKI and Its Candidacy for
Facial Clefting Anomalies
Colmenares et al. [2002] identified the
SKI proto-oncogene as likely causing
the cleft lip/palate seen in
17%
of patients with monosomy 1p36
[Heilstedt et al., 2003b]. The SKI gene
is located in the distal portion of
the monosomy 1p36 critical region.
Although 85% of Ski/ mice had
exencephaly and 15% had midline facial
clefting abnormalities instead of exen-
cephaly, an enrichment of the facial
clefting phenotype could be obtain-
ed when either 129P2 or Swiss black
352 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c ARTICLE

Figure 3. The correlation between the deletion size and the number of observed clinical features. A: This theoretical model represents
the correlation between the deletion size and the number of observed clinical features. The assumption is that the larger the deletion, the
more clinical features a patient will have. B: Findings in our study. There is no correlation between the deletion size and the number of
observed clinical features. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

Ski/ mice were backcrossed to
C57BL/6J mice. After six generations
of backcrossing with C57BL/6J, 78% of
Ski/ mice had facial clefting. The
clefting phenotype remained variable
ranging from a complete midline cleft
face, with or without cleft palate, to
a relatively mild cleft lip. Thus,
Colmenares et al. [2002] proposed that
a modifier gene(s) is likely influencing
the type of craniofacial abnormality in
Ski/ mice. All subjects that show
cleft lip and/or cleft palate are deleted for
the SKI gene. Because SKI is located in
the most distal 2 Mb of 1p, most subjects
are deleted for this gene, but only 17%
show clefting abnormalities.
The KCNAB2 Candidate Gene
for Seizures in Monosomy 1p36
Mutations in Drosophila genes that
encode either a potassium channel beta
or alpha subunit genes cause epilepsy-
like phenotypes [Stern and Ganetzky,
1989; Yao and Wu, 1999]. In humans,
mutations in potassium channel pore-
forming alpha subunits are associated
with inherited epilepsy syndromes, par-
ticularly benign familial neonatal con-
vulsions [Zuberi et al., 1999; Eunson
et al., 2000]. Given this evidence, the
potassium channel beta subunit gene,
KCNAB2, appears to be a possible
candidate for the epilepsy in monosomy
1p36. Mapping of this gene placed it
within distal 1p36 [Heilstedt et al.,
2001]. Clinical information regarding
seizures was collected on 24 subjects
with 1p36 deletions; nine subjects with
epilepsy were deleted for this gene, and
13 subjects without epilepsy were not
deleted for this gene. However, two
subjects who were not deleted for this
gene had at least one seizure episode.
Thus, if KCNAB2 is a gene causing
epilepsy, it is not the sole determinant of
epilepsy in this syndrome. It is possible
that KCNAB2 serves as a genetic
modifier to some other gene in the
deletion region. It may also be possible
that KCNAB2 is the primary gene with
other genes modifying its contribution
to the occurrence of seizures.
MMP23 and Cranial Suture
Closure in Monosomy 1p36
Recently, Gajecka et al. [2005] identi-
fied two subjects with small terminal
deletions associated with large duplica-
tions and triplications of 1p36. Both
subjects had craniosynostosis; one with
metopic and one with sagittal/coronal
craniosynostosis. Because subjects with
deletion of 1p36 have large, late-closing
anterior fontanels, and some subjects
with duplication/triplication have cra-
niosynostosis, we proposed that a gene
regulating closure of the cranial sutures is
located in 1p36. We compared the
regions of deletion, duplication, and/or
triplication between six patients that had
duplications and/or triplications in
1p36. Two subjects had craniosynostosis
and the remaining four had large, late-
closing anterior fontanels. Comparing
the regions of deletion, duplication, and
triplication revealed a 1.1 Mb region
of triplication overlap in the sub-
jects with craniosynostosis. Within this
region is the matrix metalloproteinase
23 gene (MMP23). We demonstrated
that MMP23 has expression at the
cranial sutures, and, because MMP23 is
likely involved in bone remodeling, we
proposed that MMP23 plays a role in
regulating closure of the fontanels.
Other Genes Implicated in the
Monosomy 1p36 Phenotype
Windpassinger et al. [2002] mapped the
human gamma-aminobutyric acid A
receptor delta-subunit gene (GABRD)
to 1p36.33. Because it encodes a
gamma-aminobutyric acid (GABA)
channel, the major inhibitory neuro-
transmitter in the mammalian brain, the
authors suggested GABRD as a candi-
date for the neuropsychiatric and neuro-
developmental abnormalities present in
the monosomy 1p36 phenotype.
TYPES OF
REARRANGEMENTS
Four classes of rearrangements have
been identified in monosomy 1p36:
(1) derivative, unbalanced transloca-
tions, (2) interstitial deletions, (3) appa-
rently simple terminal truncations, and
ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c
(4) complex rearrangements. Derivative,
unbalanced translocations result in a
chromosome 1 with a deleted segment
of 1p36 (partial monosomy) and a region
of another chromosome attached to the
distal end of 1p (partial trisomy). Inter-
stitial deletions are rearrangements that
result after two breaks occur proximal to
the telomere, resulting in the retention
of 1p36 telomere and the deletion of
material proximal to this region. Appa-
rently simple terminal truncations are
the least complex of the rearrangements,
in which a portion of 1p36 is lost along
with the telomere. However, the break-
points of many of the apparently simple
truncation chromosomes have not been
fully characterized and it is expected,
based on the breakpoints cloned thus far,
that many of these simple truncations are
more complex at the sequence level.
Complex rearrangements include dele-
tions with duplications, triplications,
inversions, and/or insertions.
Only 67% of de novo rearrange-
ments are apparently simple terminal
truncations at the DNA sequence
level. The remaining 33% of rearrange-
ments are complex structures including
deletions with interrupted inverted
duplications, large duplications and trip-
lications with small terminal deletions,
or more than one interstitial deletion
on a single chromosome with normal
intervening sequence. Of the 134
Only 67% of de novo
rearrangements are apparently
simple terminal truncations at
the DNA sequence level.
The remaining 33% of
rearrangements are complex
structures including deletions
with interrupted inverted
duplications, large duplications
and triplications with small
terminal deletions, or
more than one interstitial
deletion on a single
chromosome with normal
intervening sequence.
monosomy 1p36 subjects characteriz-
ed by our laboratory, 13 (9.7%) have
pure interstitial deletions; 22 (16.4%)
have unbalanced translocations (deriva-
tive chromosomes); 9 (6.7%) have com-
plex rearrangements including more
than one interstitial deletion, duplica-
tions and/or triplications; and 90
(67.2%) have apparently terminal dele-
tions. However, an unbiased assessment
of 1p36 rearrangements ascertained in a
clinical diagnostic setting reveals 7% of
rearrangements are unbalanced trans-
locations, 29% are interstitial deletions,
52% are apparently pure terminal dele-
tions, and 12% are complex rearrange-
ments [Shaffer et al., 2006; Ballif et al.,
2007].
There is no common breakpoint
location or deletion size in monosomy
1p36. Although 1p36 breakpoint(s) have
been found between 0.5 and >10.5 Mb
from the telomere, we have found at
least one cluster of breakpoints for all
four classes of rearrangements located
4–5 Mb from the 1p telomere.
Of the terminal deletions ascer-
tained by our laboratory, 46.3% are
Figure 4. Maternal and paternal distributions among cases of 1p36 deletion and
correlation with deletion size. Purple and blue bars show the deletion sizes for maternally
and paternally derived deletions, respectively. Purple and blue lines present the trend lines
for maternally and paternally derived deletions. Note that more paternally derived
deletions are among the largest deletions.
353
maternal in origin, 41.5% are paternal,
and 12.2% have an unknown origin. In
contrast, 83.3% of interstitial deletions
are maternal in origin. Most maternally
derived deletions are less than 5 Mb in
size, whereas most paternally derived
deletions are larger than 5 Mb (Fig. 4).
MONOSOMY 1P36 AS A
MODEL FOR MECHANISMS
OF TERMINAL DELETION
GENERATION AND
STABILIZATION
To date, 15 rearrangements have been
characterized at the DNA sequence level
in our laboratory [Ballif et al., 2003,
2004a,b; Gajecka et al., 2005, 2006a,b].
We identified the precise breakpoint
junctions in three subjects with appa-
rently pure terminal deletions of 1p36
ranging from 2.5–4.25 Mb. Sequencing
of the breakpoint junctions revealed one
deletion to have a simple truncation with
de novo addition of telomeric repeats
(termed telomere healing). Two subjects
had terminal deletions associated with
cryptic interrupted inverted duplica-
tions at the ends of the chromosomes.
The major mechanism stabilizing
terminal deletions of 1p36 appears to be
breakage-fusion-bridge (BFB) cycles and
may result in these terminal deletions
354 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c
with inverted interrupted duplications at
the breakpoints [Ballif et al., 2003].
Over 60 years ago McClintock
The major mechanism
stabilizing terminal deletions of
1p36 appears to be BFB cycles
and may result in these terminal
deletions with inverted
interrupted duplications
at the breakpoints.
[1939, 1941] first demonstrated in maize
that chromosomes that have lost their
telomeres form end-to-end fusions that
are subsequently broken by passage of
the newly formed dicentric chromo-
some through mitosis. The complex
chromosome structure is derived from
repeated BFB cycles during each cell
division until a stable telomeric cap is
acquired.
In addition, we found a number of
breakpoints in repetitive DNA [Ballif
et al., 2004a]. We analyzed the 1p36
deletion breakpoints at the DNA-
sequence level in four subjects with
variable-sized deletions of 1p36. All four
breakpoints fell within repetitive DNA-
sequence elements (LINEs, SINEs, etc).
This suggests that repetitive DNA-
sequence elements may play an impor-
tant role in generating and/or stabilizing
terminal deletions of 1p36. Mechanisms
by which repetitive elements may be
involved in the process of terminal
deletion formation and stabilization
include aberrant homologous recombi-
nation between similar repetitive DNA-
sequence elements [Flint et al., 1996;
Horsley et al., 2001] and illegitimate
recombination between repetitive
sequences [Katz et al., 1999].
The acquisition of a telomere from
another chromosome can occur through
a variety of mechanisms (collectively
termed ‘‘telomere capture’’) [Ballif et al.,
2004b]. Through sequence analysis at
the breakpoint junctions, we determin-
ed that the most likely mechanism for
our cases was break-induced replication
[Ballif et al., 2004b]. We propose a pre-
meiotic model for the formation of these
deletions in which a terminally deleted
chromosome is generated in the germ
line and passes through at least one BFB
cycle to produce gametes with terminal
deletions associated with interrupted
inverted duplications prior to break-
induced replication that result in the
acquired telomere. These data also sug-
gest that, on a molecular level, seemingly
pure terminal deletions visualized cyto-
genetically may be more complex than
suspected based on the appearance under
the light microscope.
We recently cloned the breakpoints
in three subjects with unrelated
der(1)t(1;9)(p36;q34) [Gajecka et al.,
2006a,b]. These derivative chromo-
somes were each inherited from a
balanced translocation carrier parent.
We characterized each derivative chro-
mosome 1 at the DNA sequence level
and identified the junctions between
1p36 and 9q34. Using cell lines from
the carrier parents of the subjects, the
junctions at the derivative chromosomes
9 were also analyzed. At the trans-
location junctions we found a number
of DNA motifs that have been impli-
cated in DNA breakage and rearrange-
ment. Among these sequences, the
DNA sequence motif recognized by
translin was found at 4 of 6 breakpoints.
Translin binding sites have been found in
disproportionately high concentrations
in or around translocation and dele-
tion breakpoint sequences [Abeysinghe
et al., 2003]. Translin has been suggested
to be a binding protein that specifically
targets consensus sequences found at the
breakpoint junctions of many trans-
locations [Kasai et al., 1997]. We also
found that the breakpoints occurred
in the high GC-content DNA on
both participating chromosomes, cor-
relating with early replication and
high gene density in the breakpoint
regions in these three cases. The break-
point regions were unique in all indi-
viduals and remarkably, interrupted
genes at all six breakpoint sites including
three known genes (BACH, SARDH,
VAV2) and three predicted genes. Inter-
estingly, two of three translocation
breakpoints showed cryptic imbalance,
ARTICLE
with duplications and insertions at the
junctions [Gajecka et al., 2006a,b].
The finding of duplications and
insertions at the translocation break-
points, and no sequence homology,
supports nonhomologous end joining
(NHEJ) as a possible mechanism for
translocation formation in these cases. In
NHEJ, two double-strand breaks (DSBs)
on apparently random chromosome
ends can simply ligate together to form
balanced or unbalanced translocations.
However, because NHEJ often involves
the insertion of nucleotide bases at the
breakpoint junctions, we have proposed
a mechanism for reciprocal transloca-
tion formation that is analogous to
the bacterial model for transposition
[Shapiro, 1979]. In this model, DSBs
occur near or at the sites that ultimately
become the junctions joining the non-
homologous ends from two chromo-
somes. The DSBs produce staggered
nicks, each breakpoint separated by the
nucleotide bases that will be duplicated
in the rearrangement stabilization/
formation. The translin motifs at the
breakpoints promote the end joining of
the broken chromosomes. Following
ligation of the broken strands, the
unpaired sequences generated by the
staggered nicks are filled in, resulting in
duplicated sequences at the breakpoint
junctions [Gajecka et al., 2006b]. Thus, a
variety of mechanisms may be involved
in the generation and/or stabilization
of 1p rearrangements; it remains to be
determined if the results obtained from
the research on 1p36 can serve as a model
for other terminal deletions.
ACKNOWLEDGMENTS
We thank Aaron Theisen for his critical
editing of the manuscript and Kyle
Sundin for his help with Figure 1
(Signature Genomic Laboratories, Spo-
kane, WA).
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