Bonaglia et al. Molecular Cytogenetics 2014, 7:53
http://www.molecularcytogenetics.org/content/7/1/53

CASE REPORTOpen AccessA new patient with a terminal de novo 2p25.3
deletion of 1.9 Mb associated with early-onset ofobesity, intellectual disabilities and hyperkinetic
disorderMaria Clara Bonaglia1*, Roberto Giorda2 and Sergio Zanini3

Abstract
Terminal and interstitial deletions of 2p25.3 (size < 3 Mb), detected by array-CGH analysis, have been reported inabout 18 patients sharing common clinical features represented by early-onset obesity/ overweightness associatedwith intellectual disabilities (ID) and behavioural troubles. This observations led to hypothesize that 2p subtelomericdeletion should be associated with syndromic obesity and MYT1L became the main candidate gene for ID andobesity since it is deleted or disrupted in all hitherto published cases.
Here we described a 2p25.3 de novo terminal deletion of 1.9 Mb, of paternal origin, detected by array-CGH analysis
in a girl of 4.4 years with a distinctive phenotype consisting of early-onset of obesity associated with moderate ID,and hyperkinetic disorder. The deletion disrupted MYT1L and encompassed five other OMIM genes, ACP1, TMEM18,
SNTG2, TPO, and PXDN.
Here, we discuss the combined functional effects of additional haploinsufficient genes, that may concur withheterozygous deletion of MYT1L, in the aetiology for syndromic obesity associated with 2p25.5 subtelomericdeletion.
Keywords: Deletion 2p25.3, Obesity, Language delay, Hypekinetic disorder, MYT1L

Background
Monosomies of 2p are very rare and are usually observed in more complex aberrations such as inverted/duplications [1], ring 2 chromosomes [2-4], or a derivative chromosome 2 ([5] one case) making a definite correlation between severity of the phenotype and size ortype of the aberrations still difficult.
Recently, terminal and interstitial deletions of 2p25.3
ranging in size from 0.37 Mb to 3.11 Mb, detected bygenome-wide array analysis, led to the definition of thesmallest region of overlap (SRO) for pure 2p25.3 deletions
in patients with intellectual disabilities (ID) [6] and earlyonset obesity [5]. This region harbours the myelin transcription factor 1-like gene (MYT1L, OMIM: 613084),
coding for a neural transcription factor with a pivotal role
* Correspondence: clara.bonaglia@bp.lnf.it
1Cytogenetics Laboratory, Scientific Institute, IRCCS Eugenio Medea, Via Don
Luigi Monza, 20, 23842 Bosisio Parini, Lecco, Italy
Full list of author information is available at the end of the article

in regulating neuron differentiation [7,8], a good candidate
gene for ID in patients with pure 2p25.3 deletion [6] andearly-onset obesity [5].
Here we report a new patient with moderate intellectual disability (ID), early-onset obesity, and hyperkinetic
syndrome associated to a 2p25.3 simple de novo terminal
deletion of 1.9 Mb disrupting MYT1L.
The causative role of MYT1L haploinsufficiency in
2p25.3 deletion and the involvement of 2pter monosomy
in the chromosomal aetiology for syndromic obesity arediscussed.

Case presentation
Informed consent was obtained from both parents of thepatient.
Frontal and lateral view of the patient as well as
growth curves are shown in Figure 1.
The patient came to our attention at the age of 3 years
for intellectual disabilities, obesity, macrosomy, and© 2014 Bonaglia et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain
Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,unless otherwise stated.

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Figure 1 Details of growth - BMI-for age and facial/physical appearance of the patient. A. On the left, growth curves for our patient
showing early-onset obesity; on the right, BMI at 41 and 53 months. The source of growth and BMI-for-age graphic is: http://www.chartsgraphs
diagrams.com/HealthCharts/growth-2-20-girls.html. B. Photographs of the patient: (a) frontal face, (b) lateral face, and (c) full frontal views. Notethe square-shaped truncal build.

hyperkinetic syndrome of unknown aetiology. She is afemale, the only child of healthy non-consanguineous
39-year-old mother and 39-year-old father with unremarkable family history. The father and mother were of
normal height and weight. She was born at 41 weeks ofgestation by caesarean section, due to spontaneous amniotic sac rupture without uterine contractions. Birth parameters were in range (weight: 3090 gr, length: 50.5 cm,
cranial circumference-OFC: 32 cm). Apgar scores were9/10 at 1′/5′, respectively. The perinatal period was unremarkable with good neonatal adaptation to extra uterine environment and breast feeding; neither hypotonia
nor jaundice were present. Her psychomotor development was characterised by sitting unsupported at15 months, walking autonomously at 18 months, anduttering her first words at 18 months. The child developed obesity during early infancy, despite normal foodseeking behaviour (Additional file 1: Table S1.) and on

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our first examination at the age of 41 months her weightwas 32 Kg (BMI = 23.59) (Figure 1A), length 128 cm(> > 97thc), OFC 51 cm (50-75thc). At the age of 3 years,
she showed mild to moderate intellectual disabilities(Leiter-R scale IQ = 79) with main deficit in the verbal
area, both in language comprehension and production.
She was able to produce less than 10 words and unable
to construct even the simplest sentences. The Vineland
Adaptive Behaviour Scale (VABS) was completed byinterviewing both parents. Patient’s age equivalent (AE)was less than 1 year 9 months; receptive language andexpressive skills score was 1 year 7 months; socialization
AE was less than 1 year 11 months; daily living skills
AE was 2 years 2 months; motor skills AE was 2 years
9 months.
Asynergistic walking with sole-sole pattern with feetintra-rotation due to intra-rotation of the tibia bilaterally
and anteroversion of the femurs’ neck has been observed.
At ocular evaluation, bilateral amblyopia (4/10) with
mixed astigmatism was observed. Audiometric examination and brain-stem auditory evoked potentials resulted within normal range, with the exception of amild delay of the 1st wave in the right ear due to mildtransmission deficits.
Electroencephalograms (EEG) recording data, acquired
during wake and spontaneous sleep, revealed epileptic
anomalies only during profound sleep.
At last evaluation, at the age of 4 y and 4 mo, her
growth parameters were: weight 39 kg (> > 97thc), length
128 cm (> > 97thc), OFC 51 cm (50-75thc), BMI 24.18(Figure 1A). Facial examination showed slightly upturned
nose and short neck without other remarkable dimorphisms (Figure 1B). Her behaviour was mainly characterised by a severe form of hyperkinetic disorder. Her
attention dwelt no more than a few minutes on a single
information or activity, even when she was extremelyinterested and highly focused on it by the examiner’sintervention. Her spontaneous play activities are basically unstructured: she holds toys, explores them rapidly
and superficially, then beats them. She appreciates
sensory-motor experiences in play. She has no play
strategies. Spontaneous interaction with relatives, other
adults, and peers is poor but present. At first glance, she
appears to be an autistic girl. However, when faced by
the examiner and stimulated by being presented toys,
she spontaneously tries to share her activities and eye
contact is present. She attends kindergarten for normally developing children; however, she has a support
teacher for the whole period of her school attendance.
She also has a special teaching schedule and program.
At present, her cognitive functioning is equivalent tomoderate mental retardation with hyperkinetic syndrome.
At last evaluation EEG, compared with the previousregistration, is remarkably better due to a significantPage 3 of 5

reduction of non-convulsive paroxysmal activity during
profound sleep.
Brain MRI showed increased subdural peri-encephalicspace in the frontal regions, and enlarged cisterna magna
without signs of compression on the 4th ventricle or thecerebellar vermis. No other remarkable signs were evident. At abdominal echography, no pathological signs
concerning spleen, liver, gallbladder, pancreas, kidneys,or bladder were observed.
Electrocardiogram (ECG) showed regular sinusoidal
rhythm with 106 bites per minute, conduction and repolarization within normal limits, QT tract corrected
385 msec, and arterial hypertension; no pathologicalsigns were evident at heart echography.
Routine haematological exams revealed increased levelsof platelets (420,000 – normal range 150,000-400,000)
increased triglycerides (217 mg/dL – normal range40–150) with normal total cholesterol (143 mg/dl- normalrange 120–140). Thyroid function was normal (TSH:1.198 μUI/ml (N:0.350-5000), T4:13.4 pg/ml (N:8.9-17.6),
and T3: 4.8 pg/ml (N:2.3-4.2)).
Array-CGH analysis, performed with an Agilent Human
Genome CGH Microarray Kit 180 k (Agilent Technologies
Inc., Santa Clara, CA) with a resolution of ~40 Kb revealed a deletion of 1.9 Mb in chromosomal band
2p25.3 (Figure 2A) including the following genes :FAM110C (OMIM *611395) ACP1 (OMIM *171500),
TMEM18 (OMIM *613200), SNTG2 (OMIM *608715),
TPO (OMIM *608715), MYT1L (OMIM *613084) PXDN(OMIM *605158) and SH3YL1, FAM150B (Figure 2B). All
nucleotide positions refer to the Human Genome, Feb
2009 Assembly (hg19). Data analysis was performed using
Agilent Cytogenomics version 2.5.8.1. The deletion breakpoint, located between 1,957,657 Mb and 1,973,115 Mb(hg19), lies within intron 6 of MYT1L.
Real-time quantitative PCR (qPCR) assays, performedon the patient and her parents using SYBR Green andanalysed on an ABI PRISM 7900HT sequence detection
system (Applied Biosystems, Foster City, CA), demonstrated that the 2p25.3 deletion originated de novo (datanot shown).
Genotyping of polymorphic locus D2S2268 in the proband and her parents, performed by amplification withprimers labelled with fluorescent probes (ABI 6-Fam and8-Hex) followed by analysis on ABI 3500AV Genetic
Analyser (Applied Biosystems), revealed the paternal
origin of the deletion (data not shown). The final interpretation of the rearrangement was arr[hg19] 2p25.3(30,341-1,957,657x1,1,973,115x2) dn.
Including the present case, about 18 patients, withages ranging from infancy to adulthood and partiallyoverlapping 2p25.3 deletions, have been described so
far [5,6]. All these patients share common distinctive
clinical features represented by early-onset obesity/

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Figure 2 Molecular details of 2p25.3 deletion. Array- CGH profile of chromosome 2 showing (A) a terminal deletion of 1.9 Mb at 2p25.3, and(B) an enlargement of the 2p25.3 deletion. Genomic view of the terminal 1.9 Mb of chromosome 2p25.3 (C): UCSC genes (GRCh37/hg19) areshown. The screenshot shows the deletion breakpoint disrupting MYT1L.

overweightness associated with ID and behavioural troubles [5,6]. The first symptom observed in our patient
was very early-onset obesity (Figure 1A), starting fromthe 3rd month of life (Additional file 1: Table S1). A
square-shaped truncal build was evident (Figure 2B), as
previously reported in four patients out of six by Steven
et al. [6] and two out of five by Doco-Fenzy et al. [5].
Her psychomotor development, resulting in mild tomoderate ID, was mainly characterized by severe language delay (less than 10 words) and inability to produce
sentences, even the simplest ones.
By combining genotype-phenotype analysis from allhitherto reported patients and DECIPHER cases, MYT1L
has recently been proposed as the major candidate genefor ID [6] and early-onset obesity [5], since the gene is deleted in all patients with terminal or interstitial monosomyof 2p25.3 [5,6]. The causative role of MYT1L haploinsufficiency for early-onset obesity is further reinforced by ourfinding, showing that our patient’s proximal deletion
breakpoint lies within a segment of 15,459 bp located in
the sixth intron of MYT1L (Figure 2C). A very similar
2p25.3 deletion of 1.975 Mb with its deletion breakpoint
within intron 5 of MYT1L has been recently reported
in another patient (PZ1 from [5]) with clinical features
overlapping those of our patient, apart from neonatal

hypotonia and failure to thrive. As hypothesized by DocoFenzy et al. [5], ACP1 and TEM18M, usually deleted in
the majority of patients with obesity or overweight, may
concur to the early-onset obesity/overweight observed inpatients with 2pter deletions. We may thus hypothesisethat haploinsufficiency of ACP1, a gene associated withsevere obesity and increased total cholesterol and triglycerides levels [9,10], may also be responsible for the increased levels of triglycerides and obesity observed in ourpatient.
Patients with small interstitial deletion involving
MYT1L (P5, SP6 and ID25513 from [5]) manifest behavioural troubles, including autistic spectrum disorders(ASD) while subjects with 2p25.3 terminal deletions
additionally involving SNTG2 (P1-2,P4 , SP5-6 from [5])manifest aggressiveness and outbursts [5,6,11].
Our patient carrying a 2p25.3 deletion spanning ninegenes, including SNTG2 and MYT1L (Figure 2B) manifests neither ASD nor aggressiveness and outburst. Her
spontaneous interaction with relatives, other adults, andpeers is poor but present and, if stimulated, she spontaneously tries to share her play activities. Her behaviour ismainly characterised by a severe form of hyperkinetic disorder. Overall, hyperactivity appears to be the main behavioural trait observed in patients with 2p25.3 monosomy.

Bonaglia et al. Molecular Cytogenetics 2014, 7:53
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Conclusions
In conclusion, we identified a de novo 1.9 Mb deletion of
2p25.3 in a girl with distinctive phenotype characterisedby early-onset obesity, ID, and hyperkinetic disorder.
The deletion breakpoint disrupting the MYT1L gene reinforces the hypothesis of its primary causative role inID, hyperactivity, and obesity.
MYT1L is disrupted or entirely deleted in all hitherto reported patients with subtelomeric 2pter microdeletions.
Combined functional effects of additional multiple
haploinsufficient genes, usually deleted in patients with
2p25.3 monosomy, may concur to cause the observed
clinical signs. Our data further reinforce the notion that
subtelomeric 2p25.3 deletion (size < 3 Mb) results insyndromic obesity.
ConsentWritten informed consent was obtained from the parentsof the patient for publication of this Case Report and any
accompanying images. A copy of the written consent isavailable for review by the Editor-in-Chief of this journal.
Additional file
Additional file 1: Table S1. Growth curves of the patient.

Competing interests
The authors declare that they have no competing interests.

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doi:10.1186/1755-8166-7-53
Cite this article as: Bonaglia et al.: A new patient with a terminal denovo 2p25.3 deletion of 1.9 Mb associated with early-onset of obesity,
intellectual disabilities and hyperkinetic disorder. Molecular Cytogenetics
2014 7:53.

Authors’ contributions
MCB performed array-CGH analysis and wrote the paper; RG performed qPCRand microsatellite analysis; SZ was responsible for the patient’s clinicalfollow-up examination and contributed to the clinical description. All authors
read and approved the final manuscript.
Acknowledgments
We would like to gratefully acknowledge the family participating in thisstudy.
Author details
1Cytogenetics Laboratory, Scientific Institute, IRCCS Eugenio Medea, Via Don
Luigi Monza, 20, 23842 Bosisio Parini, Lecco, Italy. 2Molecular Biology
Laboratory, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco,Italy. 3Unit for Severe Disabilities in Developmental Age, Scientific Insitute,
IRCCs Eugenio Medea, Udine, Italy.
Received: 6 June 2014 Accepted: 17 July 2014
Published: 5 August 2014
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