Original article
pISSN 2635-909X • eISSN 2635-9103
Ann Child Neurol [Epub ahead of print]
https://doi.org/10.26815/acn.2020.00108

Deep Phenotyping in 1p36 Deletion Syndrome
Youngkyu Shim, MD1, Young Jun Go, MD1, Soo Yeon Kim, MD1,2, Hunmin Kim, MD3, Hee Hwang, MD3, Jieun
Choi, MD4, Byung Chan Lim, MD1,2, Ki Joong Kim, MD1, Jong-Hee Chae, MD1,2
1

Department of Pediatrics, Pediatric Clinical Neuroscience Center, Seoul National University Children’s Hospital, Seoul National University
College of Medicine, Seoul, Korea
2
Research Center for Rare Diseases, Seoul National University Hospital, Seoul, Korea
3
Department of Pediatrics, Seoul National University Bundang Hospital, Seongnam, Korea
4
Department of Pediatrics, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea
Received: May 26, 2020
Revised: July 7, 2020
Accepted: July 14, 2020
Corresponding author:
Jong-Hee Chae, MD
Department of Pediatrics, Seoul
National University Children’s
Hospital, Seoul National University
College of Medicine, 101 Daehakro, Jongno-gu, Seoul 03080, Korea
Tel: +82-2-2072-3622
Fax: +82-2-743-3455
E-mail: chaeped1@snu.ac.kr

Purpose: Although 1p36 deletion syndrome is the most common terminal deletion syndrome, unexplained phenotypic variability still occurs. We aimed to delineate the phenotype of this syndrome in detail and to characterize the phenotype-genotype correlation.
Methods: We retrospectively reviewed 15 patients diagnosed with 1p36 deletion syndrome confirmed by chromosomal microarray.
Results: All 15 patients revealed delayed attainment of motor milestones and speech. Seven patients (46.7%) never walked alone and only two (13.3%) could express a simple two-word sentence. They all showed subsequent intellectual disability. Two patients with large deletions ofboth distal and proximal critical regions of the 1p36 region shared severe intellectual disability
with Rett syndrome-like behavioral features. Seizures, although frequent (73.3%), were well-controlled except in one patient with infantile spasms. Facial dysmorphism (92.9%) and ventricular
mild dilatation with corpus callosum anomaly (46.7%) were common. Heart problems were identified in 14 patients, including structural abnormalities and/or functional problems associatedwith the gene encoding PR domain-containing protein 16. Two patients developed severe cardiac
dysfunction requiring heart transplantation in their late teens. One patient with a 400 Kb deletion partly overlapping with the gene encoding calmodulin-binding transcription activator 1 did
not have facial dysmorphism and presented with mild developmental delay and ataxic gait. One
patient had a choledochal cyst, which was resected due to neonatal cholestasis.
Conclusion: Although the phenotype of 1p36 deletion syndrome is quite consistent with previous
reports, additional manifestations such as certain behavioral features, ataxic gait, and severe cardiac dysfunction at an early age should be considered.
Keywords: Chromosome 1p36 deletion syndrome; Phenotype; Genotype

Introduction
The 1p36 deletion syndrome (OMIM 607872, also referred to as
monosomy 1p36 syndrome) is the most common chromosome
terminal deletion syndrome. This syndrome has some notable fea-tures. The estimated prevalence ranges from 1 in 5,000 to 1 in
10,000 [1-3]. Previous reports described the characteristic featuresof 1p36 deletion syndrome, which include developmental delay/
intellectual disability (ID), epilepsy, craniofacial anomaly, andstructural or functional heart problems [1,4,5]. However, some

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Shim Y et al. • Phenotype of 1p36 Deletion Syndrome

unexplainable phenotype variability still occurs. It is important todelineate clinical and genetic heterogeneity in terms of earlier recognition of the disorder, individualized surveillance testing forco-morbidities, and counseling on the prognosis. Recent advanced
chromosomal microarray (CMA) enables physicians to detect interstitial deletions located in the far proximal site, identify complex
rearrangements of the deletion site, and measure the extent of thedeletion, which can precisely identify the involved genes comparedto G-banded chromosomal analysis or telomere fluorescence insitu hybridization. We report our patients’ phenotypic spectrum of
the 1p36 deletion syndrome with noticeable findings along withthe exact breakpoint of chromosomes as detected by CMA. We
also attempted to compare our results to previously reported findings in other literature.

Materials and Methods
Fifteen patients diagnosed with the 1p36 deletion syndrome byusing CMA were retrospectively reviewed. The CMA test was
conducted using Agilen Human Genome oligonucleotide comparative genomic hybridization microarray 244, 80, or 60 K (Agilent
Technologies, Santa Clara, CA, USA) with 8.9, 13, or 41 Kb overall median probe spacing, respectively. All copy number variants
were called and based on human assembly GRCh37 (hg19). Thirteen patient’s CMA data with exact chromosome deletion size andlocation were demonstrated with involved genes. Two patients’clinical characteristics without detailed CMA data were also reviewed in attempt to review the phenotype variability. This study
was approved by the Institutional Review Board of Seoul National
University hospital (IRB No: H-2005-143-1125). Informed consent was waived by the board.
Patients’ clinical characteristics and ancillary tests were retrospectively reviewed. Available cerebral magnetic resonance imaging (MRI), electroencephalography, echocardiography, abdominal
ultrasonography, and laboratory results were all reviewed. Phenotypes with related genetic breakpoints and responsible genes described in previous literature were analyzed

Results
1. Patients’ demographics
Of the 15 patients we recruited into the study, nine were female
and six were male, giving a female to male ratio was 3:2. The median age at diagnosis was 4 years and ranged from 2 months to 15
years. The median follow up duration was 4.5 years and ranged
from 0.8 to 9.9 years. All patients were aged more than 4 years andfour patients were over 18 years old at the last follow-up. Eight pa2

tients’ parental tests were available and all were reported as de novodeletions in the 1p36 region. All 15 patients’ demographic data andoverall clinical features are provided in Table 1.

2. Neurological problems
All 15 patients were reported to have varying degrees of developmental delay or ID. Delayed attainment of motor milestones andspeech was apparent in all 15 patients. Although all patients could
Table 1. Overview of the clinical features of the 15 patients with
1p36 deletion (n=15)
Variable
Female sex
Age at diagnosis (yr)Follow-up duration (yr)Age at last follow-up (yr)DD or ID
No ambulation
Walking with or without assistance
Aphasia or a few words
Sentence expression
SeizureSeizure onset age (mo)Facial dysmorphism
Brain abnormality
Corpus callosum abnormality
Ventricular dilatation
Simplified gyral pattern
PVWM T2HSI
Migration anomaly
Heart problems
PDA
ASD or VSD
LVNC or CMP
Valve problems
Needed treatment (operation or medication)
Finger or toe abnormalitya
Eye problems
Hearing loss
Cryptorchidism
Choledochal cyst
Inguinal hernia
Hypothyroidism
Type 2 diabetes mellitusValue
9 (60)
4.0 (0.2–15.0)
4.5 (0.8–9.9)
8.5 (4.4–21.1)
15 (100)
7 (46.7)
8 (53.3)
13 (86.7)
2 (13.3)
11 (73.3)
8 (2-204)
13/14 (92.9)
10/12 (83.3)
4
3
3
2
1
14/14 (100)8642
9/14 (64.3)
7
4
4
3
1
1
1
1

Values are presented as number (%) or median (interquartile range).
DD, developmental delay; ID, intellectual disability; PVWM T2HSI,
periventricular white matter T2 high signal intensity; PDA, patent ductus
arteriosus; ASD, atrial septal defect; VSD, ventricular septal defect; LVNC,
left ventricular noncompaction; CMP, cardiomyopathy.
aOverriding, curly, or contracture deformity of fingers or toes.
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Ann Child Neurol [Epub ahead of print]

sit with or without support eventually, seven patients (46.7%) were
not able to get walking ability even after their age of 4 years. Thosepatients also showed limited language acquisition. At the most, a
few word expression was possible. Eight patients (53.3%) could
walk with or without assistance; however, only two patients wereable to express a simple sentence consisting of two basic words.
One patient (Patient 6) with the smallest chromosome deletion(400 Kb, chr1:6499296-6900414) who presented with slow catchup development could walk alone at his age of 31 months and revealed the mildest ID among 15 participants. Other 14 patients
showed severe ID without developmental regression (Table 2).
A noticeable feature was found in two relatively older children
aged 10 and 13 years that visited (Patient 2 and 3, respectively).
They presented with Rett syndrome-like behavioral features including severe ID with hand automatism or bruxism showed large
deletions that overlapped both distal [6] and proximal [7] criticalregions. Other behavioral features such as aggressive behavior (Patient 5) and attention deficit hyperactivity disorder (Patient 6)
were also described. The available CMA data of thirteen patientsare depicted in Fig. 1.
Seizures occurred in 11 patients (11/15, 73.3%). Every firsttime seizure occurred before the age of five except in one patient(Patient 2, seizure onset at 17 years old). In seven patients (63.6%),
seizure was noticed before the age of one and the earliest onset age
was 2 months. Seizure semiology was variable, including focal

clonic, generalized tonic or clonic, hypomotor, or spasm. Only one
patient (Patient 1) had infantile spasms and was detected hypsarrhythmia in electroencephalography. Combination of vigabatrin,zonisamide, and prednisolone were required in this patient whose
deletion size was the largest one (10.5 Mb) of all the study participants. Except in this patient, seizures were well-controlled withzero (n = 2) to two (n = 2), mostly one (n = 6), antiepileptic drug
(AED). Three patients were able to discontinue AED after 3 years
from their initial treatment. There was no correlation between seizure onset age and seizure severity.

3. Facial dysmorphism
Facial dysmorphism was noticed in 13 patients with flat and palefaces, deep-set eyes, small-slit eyes, hypertelorism, flat noses andnasal bridges, low set ears with small or large cupped ears, thickened ear helices, small mouths, or pointed chins. Although somepreviously delineated dysmorphic facial features were noticed, we
could not identify any shared facial anomaly between the patients.
There was no relationship between the deletion sizes and facial
dysmorphism. However, one patient (Patient 6) with the smallest
size of deletion (400 Kb) did not have any apparent craniofacial
anomaly.
4. Brain structural abnormality
Brain structure was able to assess in 12 patients with MRI. Among

Table 2. Neurologic characteristics of the 15 patients with 1p36 deletion syndrome
No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15

Age at last FU (yr)
7.2
20.7
21.1
8.9
5.1
8.5
10.9
4.6
9.5
6.2
19.0
4.1
19.6
4.4
5.5

Walka
+
+
+
+
+
+
+
+
-

Sentenceb++-

Behavior Seizure onset
Seizure typec
AEDd
NA
2 mo
Spasm, hypomotor VGB ZNS (PD)RS-like
17 yr
Tonic
CLB VPA LTG
RS-like
1 yr
NA
VPAAggressive
4 yr
Hypomotor
VPA
ADHD
4 yr
Hypomotor
NA
NA
3 mo
Clonic, hypomotor
VPA OXC
NA
2 mo
NA
VPA
NA
NA
NA
NA
2 mo
Focal clonic
LEV
NA
3 yr
Tonic
NA
NA
NA
NA
NA
4 mo
NA
LEV CLB

FD
+
+
+
+
+
+
+
+
+
+
+
+
+
n/a

Brain MRICC hypoplasia, Vd, SGVd
CC dysgenesis
Migration anomaly
SG
NormalCC splenium dysgenesis
NA
CC rostrum dysgenesis, Vd
NormalNormalPVWM T2 high signal
SG
NA
NA

FU, follow-up; AED, antiepileptic drug; FD, facial dysmorphism; MRI, magnetic resonance imaging; NA, not available; VGB, vigabatrin; ZNS, zonisamide;PD, prednisolone; CC, corpus callosum; Vd, ventricular dilatation; SG, simplified gyral pattern; RS, Rett syndrome; CLB, clobazam; VPA, valproate; LTG,
lamotrigine; ADHD, attention deficit hyperactivity disorder; OXC, oxcarbazepine; LEV, levetiracetam; PVWM, periventricular white matter.
aAble to walk with or without assistance at the last follow-up; bAble to speak a sentence at the last follow-up; cGeneralized seizures, unless otherwise
described; dUnderlining indicates prescribed medications at the last follow-up.
https://doi.org/10.26815/acn.2020.00108

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Shim Y et al. • Phenotype of 1p36 Deletion Syndrome

1p36.3301

1p36.322

3

4

1p36.315

6

1p36.2378

1p36.22
9

10

11

12 Mb

CAMTA1UBE4B
RERE
KCNAB2
PRDM16SKIGABRD
MMP23B
Proximal CR
Distal CR
Patient 1
Patient 2
Patient 3
Patient 4
Patient 5
Patient 6
Patient 7
Patient 8
Patient 9
Patient 10
Patient 11
Patient 12
Patient 13

Fig. 1. Chromosomal terminal deletion of the 1p36 region in 13 patients with candidate gene locations. Thirteen patients’ chromosome
breakpoint and location data are depicted based on available chromosomal microarray test results. Each solid bar represents the deletion
point and size. Interstitial deletion is illustrated with a solid green bar. Previously reported proximal/distal critical regions (CRs) andknown candidate genes are shown in solid red and blue color bars, respectively. Calmodulin binding transcription activator 1 (CAMTA1;
chr1: 6,845,384-7,829,766) was partially deleted (chr1: 6845384-6900414) in patient 6. Other previously reported candidate genes arealso depicted with their size and location. UBE4B, ubiquitination factor E4B; RERE, arginine-glutamic acid dipeptide repeats; KCNAB2,
potassium voltage-gated channel subfamily A regulatory beta subunit 2; PRDM16, PR domain-containing protein 16; SKI, SKI protooncogene; GABRD, gamma-aminobutyric acid receptor delta; MMP23B, matrix metalloproteinase 23B.

them 10 patients (83.3%) had some abnormalities including four
patients with corpus callosum abnormalities (hypoplasia or dysgenesis), three patients with ventricular dilatation, three patientswith simplified gyrus patterns, two patient with periventricularwhite matter T2 high signal intensity, and one patient with migration anomaly. Two patients including one patient (Patient 6) withthe smallest size of interstitial deletion (400 Kb) did not have any
brain structural abnormality.

5. Heart problems
Except for one patient who did not undergo echocardiography, allpatients had a certain degree of heart anomalies or functional problems. Patent ductus arteriosus was the most common problem(57.1%) followed by atrial septal defect (ASD) or patent foramen
ovale (35.7%), ventricular septal defect (VSD; 28.6%), left ventricular noncompaction (LVNC), or dilated cardiomyopathy(DCMP; 28.6%), and valve anomaly (14.3%; severe mitral valve
stenosis, bicuspid aortic valve). Nine patients required either corrective operations for cardiac anomalies or pharmacological treatments for cardiac dysfunction (9/14, 64.3%). Of the three patients(Patient 7, 11, and 13) with DCMP, two patients (Patient 11 and13) had end-stage cardiac dysfunction impending heart transplantation at their ages of 19.6 and 19.0 years, respectively. All four patients with either LVNC or DCMP revealed that their deleted
chromosome sites were involved with the gene encoding PR domain-containing protein 16 (PRDM16), previously well known as
4

one of the major genes responsible for cardiomyopathy. Patient 6,
with the smallest interstitial deletion (400 Kb), had ASD and VSD.
However, those defects did not require any treatment, and closed
spontaneously.

6. Other phenotypes
Almost half of the patients (7/15, 46.7%) had either finger or toe
anomaly. The phenotypic descriptions were either overriding,curly, or contracture deformity of fingers or toes. Amblyopia or esotropia was also found in four patients. Sensory neural hearing loss
was another problem in four patients. Cryptorchidism (n= 3), inguinal hernia (n = 1), hypothyroidism (n = 1), and type 2 diabetes
mellitus (n = 1) were reported as well. A choledochal cyst withneonatal cholestasis was observed in Patient 12. None of them wasreported to have neuroblastoma. The patients’ non-neurologicalclinical phenotypes were provided in Table 3.

Discussion
In patients with the 1p36 deletion syndrome, a certain phenotype
with a responsible deleted region or a causative gene was still underinvestigation along with cumulating CMA data [5,8]. Although
deletion size is not linearly correlated with the clinical severity, critical regions and involved genes in 1p36 region were reported inprevious studies [7-10].
Moderate to severe ID is present universally in the patients withhttps://doi.org/10.26815/acn.2020.00108

Ann Child Neurol [Epub ahead of print]
Table 3. Detailed non-neurologic phenotypes of the 15 patients with 1p36 deletion syndrome
No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15

Age at last FU (yr)
7.2
20.7
21.1
8.9
5.1
8.5
10.9
4.6
9.5
6.2
19
4.1
19.6
4.4
5.5

Heart problem
Limb anomaly
PDAa
Overriding toe
Closed PDA, VSD
Clinodactyly
NA
Hand deformity
PDAa, bicuspid AV
Curly toe
Large PDA, severe MSa
Closed ASD, VSD
DCMPbClinodactyly
ASD
VSD, ASD
LVNC, PFO
PDAa, DCMPb, arrhythmiab Finger contracture
PDAa, small ASD or PFOb
DCMPOverriding toe
VSD, ASD, PDAa
PDAa-

Eye problem
Amblyopia
Amblyopia
Amblyopia
Esotropia-

Hearing loss
+
+
+
+
-

GI or GU problem Endocrine problem
CryptorchidismaaInguinal hernia
Cryptorchidism
Cryptorchidism
Choledochal cysta Hypothyroidismb
T2DMb-

FU, follow-up; GI, gastrointestinal; GU, genitourinary; PDA, patent ductus arteriosus; VSD, ventricular septal defect; NA, not available; AV, aortic valve; MS,mitral valve stenosis; ASD, atrial septal defect; DCMP, dilated cardiomyopathy; LVNC, left ventricular noncompaction; PFO, patent foramen ovale; T2DM, type2 diabetes mellitus.
aManaged with surgical methods; bManaged with medications, including two patients (marked in bold) with end-stage cardiac dysfunction.

1p36 deletion syndrome [1]. Shimada et al. [8] described the genomic regions responsible for ID and associated possible modifier
genes, potassium voltage-gated channel subfamily A regulatory
beta subunit 2 (KCNAB2; chr1:6,052,358–6,161,253; OMIM#
601142). They reported that patients with terminal deletions larger than 6.2 Mb from telomere showed no ambulation and poor
prognosis of neurodevelopmental status. We noticed the similarfindings in our five patients (Patient 1 to 5) with larger deletions
including KCNAB2 gene. They were having severe neurocognitive
delay prominent with speech delay and not able to gain walking
ability at last follow-up in their age of 7, 20, 21, 8, and 5 years, respectively. Patient 14 (4 years old) and 15 (5 years old) were notable to walk at their last follow-up; however, no detailed information of deletion size was available. We could assume that theymight have larger than 6.2 Mb deletions.
Behavioral problems were not easy to be specified due to severe
ID. However, an unknown cause of female ID with Rett syndrome
like behavioral features could be another behavioral phenotype of
the 1p36 deletion syndrome. Patients 2 and 3 presented with severe ID with hand automatism, bruxism, and abnormal breathing
pattern. It was clinically indicated Rett syndrome. In contrast toRett syndrome, they showed early onset developmental delay
without regression and mild anomalies in face, fingers, or brain. Patients 2 and 3 were tested negative for the MECP2 deletion/duplication and had large deletions of 9.9 and 9.8 Mb, respectively in the
1p36 region. This finding is another possible behavioral expression
https://doi.org/10.26815/acn.2020.00108

of the 1p36 deletion syndrome along with the Prader-Willi syndrome-like behavioral expression [11,12]. Further investigation ofgenes responsible for behavioral expressions should be performedin the future study.
Seizures were a common manifestation reported from 50% to
79% [1,4,8]. Infantile spasms and refractory epilepsy (20.9%) wereassociated with poor clinical outcomes in a previous study [13].
Our study also showed a high rate of occurrence of seizures(11/15, 73.3%). However, except for one patient presenting with
infantile spasms having the largest deletion size, seizures were
well-controlled, or even resolved spontaneously. Four patientswere required AED at last follow-up and their deletion size wereover 5.9 Mb. Although it demands a larger cohort study to establish statistical significance, the severity of seizure seems to be related to the size of the deletion rather than to the onset age of the seizure.
We noted that each patient had some shared facial appearanceswith reported features. However, not all patients were able to besuspicious of the 1p36 deletion syndrome based on facial features
only. There was no specific pattern of congenital brain structuralabnormality either. One patient (Patient 6) with a small interstitialdeletion of 400 Kb (chr1:6499296-6900414) showed a normal facial appearance and brain structure.
Cardiac assessment is crucial at initial evaluation and also during
long term follow-up period in 1p36 deletion syndrome. Structuralanomaly with or without left ventricular dysfunction is a major
5Shim Y et al. • Phenotype of 1p36 Deletion Syndrome

concern in 1p36 deletion syndrome patients in view of their longterm prognosis. Previous literature reported heart problems asprevalent manifestations with up to 75% of structural anomaly and
23% to 31% of cardiomyopathy [4,5,14]. Our report showed thepossible severity of cardiomyopathy as an end-stage severe heart
dysfunction in two patients. These two patients were impending
heart transplantation as they were approaching adulthood. Cardiac
dysfunction in two other patients was not severe; however, the older patient required medications at the age of 10 years during thelast follow up. Due to well-controlled seizures in early childhood
and absence of symptoms with slowly progressing heart dysfunction, follow up might be irregular, and as such early prophylactic
medical treatment may be missed. Encouraging regular follow-up
with explanations of possible heart involvement in 1p36 deletion
syndrome in late teenage should be included in patients’ and parents’ education, even in a patient without any symptom or sign.
One patient (Patient 6) with a small interstitial deletion of 400
Kb (chr1:6499296-6900414) was presented with relatively mild
phenotype, including mild global developmental delay, ataxic gait,
unilateral crytorchidism, amblyopia, and spontaneously-closed
ASD and VSD. Brain MRI was normal and he had no history of
seizure. The deleted position revealed 11 involved genes including
three high pLI (loss of function intolerance) genes; PHD finger
protein 13 (PHF13), DnaJ heat shock protein family member C11(DNAJC11), calmodulin-binding transcription activator 1 (CAMTA1). Among them, CAMTA1 was previously reported as thecause of non-progressive congenital ataxia with or without ID[15,16], which was consistent with the phenotype of this patient
having mild global developmental delay and unexplainable ataxic
gait. This deleted region was not regarded as a critical region in theprevious literature. This patient showed amblyopia and cryptorchidism as well. However, there was no shared deleted region among
patients who had amblyopia and cryptorchidism. This finding
might be another explanation for the shared phenotype with different involved genes [17].
The 1p36 deletion syndrome showed a tendency of contiguous
gene deletion syndrome presenting a more severe phenotype incase of larger deletion size. However, there was often discordance
between deletion size and clinical features. Even cases with smalldeletion sizes had most of the clinical features of 1p36 deletion
syndrome [4]. It is a reasonable assumption that the distal part ofthe 1p36 region is responsible for distinct features of the 1p36 deletion syndrome. Beyond this very critical terminal region, continuous efforts to delineate phenotype variability with exact genotyping is crucial in a variable range of deletion sizes, and an inconsistent breakpoint of the chromosome 1p36 region.

6

Conflicts of interest
No potential conflict of interest relevant to this article was reported.

ORCID
YoungKyu Shim, https://orcid.org/0000-0002-3414-4702
Young Jun Go, https://orcid.org/0000-0002-1680-720X
Soo Yeon Kim, https://orcid.org/0000-0003-2240-3647
Hunmin Kim, https://orcid.org/0000-0001-6689-3495
Hee Hwang, https://orcid.org/0000-0002-7964-1630
Jieun Choi, https://orcid.org/0000-0001-6845-8745
Byung Chan Lim, https://orcid.org/0000-0002-8509-4135
Ki Joong Kim, https://orcid.org/0000-0002-0849-125X
Jong-Hee Chae, https://orcid.org/0000-0002-9162-0138

Author contribution
Conceptualization: YS, YJG, SYK, HK, HH, JC, BCL, KJK, andJHC. Data curation: YS, YJG, SYK, HK, HH, JC, BCL, KJK, andJHC. Formal analysis: YS, SYK, and JHC. Methodology: YS, SYK,and JHC. Project administration: YS. Visualization: YS. Writing-original draft: YS. Writing-review & editing: YS and JHC

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