University of Southern Denmark
A new 1p36.13-1p36.12 microdeletion syndrome characterized by learning disability,
behavioral abnormalities, and ptosis
Aagaard Nolting, Line; Brasch-Andersen, Charlotte; Cox, Helen; Kanani, Farah; Parker,
Michael; Fry, Andrew E.; Loddo, Sara; Novelli, Antonio; Dentici, Maria Lisa; Joss, Shelagh;
Jørgensen, Joan P.; Fagerberg, Christina R.
Published in:
Clinical Genetics
DOI:
10.1111/cge.13739
Publication date:
2020
Document version:
Accepted manuscript
Citation for pulished version (APA):
Aagaard Nolting, L., Brasch-Andersen, C., Cox, H., Kanani, F., Parker, M., Fry, A. E., Loddo, S., Novelli, A.,
Dentici, M. L., Joss, S., Jørgensen, J. P., & Fagerberg, C. R. (2020). A new 1p36.13-1p36.12 microdeletion
syndrome characterized by learning disability, behavioral abnormalities, and ptosis.
Clinical Genetics
,
97
(6),
927-932. https://doi.org/10.1111/cge.13739
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10.1111/cge.13739
A new 1p36.13-1p36.12 microdeletion
syndrome characterized by learning disability,
behavioral abnormalities, and ptosis
Short running title: 1p36.13-1p36.12 deletion syndrome
Line Nolting
1
, Charlotte Brasch-Andersen
1
, Helen Cox
2
, Farah Kanani
3
, Michael Parker
3
, Andrew E.
Fry
4
, Sara Loddo
5,
Antonio Novelli
5
, Maria Lisa Dentici
6
, Joss Shelagh
7
, Joan P. Jørgensen
8
, Christina
R. Fagerberg
1
Affiliations
1
Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
2
West Midlands Regional Clinical Genetics Unit Birmingham U.K, Birmingham, United Kingdom.
3
Sheffield Clinical Genetics Service, Northern General Hospital, Sheffield, United Kingdom.
4
Institute of Medical Genetics, University Hospital of Wales, Heath Park, Cardiff, United Kingdom.
5
Laboratory of Medical Genetics,
Bambino Gesù Childrens' Hospital, Rome, Italy.
6
Medical Genetics Unit, Bambino Gesù Children's Hospital, Rome, Italy.
7
Clinical Genetics, West of Scotland Genetic Services, the Queen Elisabeth University Hospital,
Glasgow, United Kingdom.
8
Hans Christian Andersen Children’s Hospital, Odense University Hospital, Odense, Denmark
Corresponding author
Christina Ringmann Fagerberg, christina.fagerberg@rsyd.dk
Acknowledgements
We thank the patients and their families for their kind participation. This study makes use of data
generated by the DECIPHER community. A full list of centres who contributed to the generation of
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[Skriv her]
the data is available from http://decipher.sanger.ac.uk and via email from decipher@sanger.ac.uk.
Funding for the project was provided by the Wellcome Trust.
Conflict of interest
The authors declare no conflicts of interest.
Data Available Statement
Not relevant. Most deletions can be seen in Decipher.
Abstract
Two 1p36 contiguous gene deletion syndromes are known so far: the terminal 1p36 deletion
syndrome, and a 1p36 deletion syndrome with a critical region located more proximal at 1p36.23-
1p36.22. We present even more proximally located overlapping deletions from seven individuals,
with the smallest region of overlap comprising 1 Mb at 1p36.13-1p36.12 (chr1:19077793-20081292
(GRCh37/hg19)) defining a new contiguous gene deletion syndrome. The characteristic features of
this new syndrome are learning disability or mild intellectual disability, speech delay, behavioral
abnormalities, and ptosis. The genes UBR4 and CAPZB are considered the most likely candidate
genes for the features of this new syndrome.
Keywords
Chromosomes, Human, Pair 1; Ptosis; Chromosome Deletion; Learning disability; Behavioral
abnormality
Introduction
1p36 terminal deletion is considered the most common terminal deletion in humans with an incidence
of 1 in 5000 newborns.
1-3
Partial monosomy of chromosome 1p36 was first described in 1980, and in
1997 Shapira et al. delineated the 1p36 deletion syndrome.
4
The phenotype is variable with the most
common features being intellectual disability, hypotonia, craniofacial dysmorphic features, growth
delay, eye/vision problems, seizures and hearing impairment.
4
Wu et al (1999) found the critical
region to be of 6.29 Mb at 1p36.33-1p36.31 (chr1:1-6289973).
5
In 2007 Kang et al defined a more
proximal distinct 1p36 deletion syndrome with a critical region of 2.24 Mb at 1p36.23-1p36.22
(chr1:9124551-11362893) in five patients.
6
The features linked to this region were cognitive deficits,
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[Skriv her]
congenital malformations, hirsutism, frontal and parietal bossing, epicanthic folds, and broad and
arched eyebrows.
6
We present seven individuals from five families with even more proximally
located overlapping interstitial deletions in 1p36.13-1p36.12 and define this as a third contiguous
gene deletion syndrome linked to 1p36.
Material and methods
Cases with overlapping deletions in 1p36 were identified via the DECIPHER Database (Database of
Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources).
7
Only individuals
with isolated deletions less than 5 Mb were included in the study. The literature was reviewed to
identify individuals with isolated overlapping 1p36 deletions.
Consent for publication of clinical features and photos were obtained from all individuals shown in
figure 1.
Candidate genes in the smallest region of overlap (SRO) were selected as OMIM genes with a pLI
score > 0.8 (pLI = probability of LoF intolerance) in the Genome Aggregation database (GnomAD,
accession date July 2nd, 2019).
8
Results
Clinical features are listed in Table 1, and a summary of clinical features can be seen in Table 2.
Detailed case descriptions can be seen in supplementary material.
Photos and schematic presentation of the 1p36 deletions are shown in Figure 1.
The SRO for individuals presenting with learning disability or mild intellectual disability, behavioral
anomalies, and ptosis encompassed 1 Mb at chr1:19077793-20081292 (GRCh37/hg19). Individual 8
was described as non-dysmorphic and had a limited overlap with the SRO of 66 bp. She was not
considered having the new microdeletion syndrome and her presence might indicate that the SRO
could be even smaller.
The father of individual 3 was not available for analysis, and the mother did not have the deletion.
The array data of individual 3 revealed 35 SNPs in the region of the deletion. Nine of 35 SNPs were
not maternally inherited, and the deletion was concluded to be of the maternal allele. The remaining
SNPs were non-informative but in concordance with loss of maternal allele. As the mother did not
have the deletion, we conclude, that the deletion arose de novo in individual 3. The inheritance was
thus known in all seven individuals.
Discussion
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[Skriv her]
We present seven individuals with overlapping deletions in 1p36.13-1p36.12 and define a new
microdeletion syndrome in 1p36 located more proximal to those previously described.
Four individuals were females, three were males. Five deletions occurred de novo (71%) while two
siblings had inherited the deletion from their mother (29%). The majority was born at term and had a
birth weight in the lower normal range. Postnatal growth was normal for all except one. Learning
disability or mild intellectual disability was present in all except one who had moderate intellectual
disability. Motor problems, behavioral anomalies and speech delay were seen in most individuals.
Behavioral anomalies were seen in 57% (4/7), two of whom were diagnosed with ADHD.
Dysmorphic features seen in at least 50% were congenital ptosis, pointed chin, high palate,
misalignment of teeth, and epicanthus. Ophthalmologic features were seen in all (7/7), of which
congenital ptosis – unilateral or bilateral – was the most distinct finding seen in 5/7 individuals (71%).
Less frequent were hypermetropia, epicanthus, deep-set eyes, and heavy eyebrows. Mild hearing loss
was seen in one individual. Present in 50% or less were congenital heart defect (ASD and/or VSD,
pulmonary valve dysplasia), and features of hands and feet such as clinodactyly, syndactyly,
camptodactyly, and arachnodactyly.
Congenital ptosis is a distinct feature seen in more than half of the individuals. Ptosis is defined as
the upper eyelid being positioned lower than normal, thereby narrowing the palpebral fissures vertical
axis. Ptosis is considered congenital, when present before one year of age. Congenital ptosis can result
in abnormal visual function and development, such as amblyopia. The levator palpebra superior
muscle which elevates the upper eyelid is innervated by the 3
rd
cranial nerve, n. oculomotorius. The
pathophysiologic process leading to ptosis can be either neurogenic, myogenic, aponeurotic or
mechanical
9
. Congenital ptosis can occur isolated or as part of a syndrome. Congenital isolated ptosis
most often occurs sporadically but can also be familial, and several loci and candidate genes have
been suggested, including 1p32-1p34.1
10
, Xq24–27.1
11
, and the ZFH4 gene at 8q21.12.
9
Congenital
ptosis can be part of numerous genetic syndromes
12
, some examples are congenital fibrosis of the
extraocular muscles (KIF21A, PHOX2A, TUBB3)
13
, SIX2 haploinsufficiency
14
, various types of
myopathy
15
, neurogenetic diseases
16
, and mitochondrial diseases.
17
The 1p36.13-1p36.12
microdeletion syndrome presented here is a new syndrome with ptosis as a distinct feature.
Haploinsufficiency of one or more genes in this region is suspected to cause ptosis, but the relevant
gene/genes and pathophysiological process are unknown.
The smallest region of overlap (SRO) encompasses 1 Mb at chr1:19077793-20081292. The SRO
contains several genes, none of which are currently known to be haploinsufficient. The following
genes, being the only ones with a pLI-score above 0.8, are suggested as possible candidate genes for
features of this new microdeletion syndrome:
The UBR4 gene (OMIM 609890), encodes a mammalian N-recognin.
18
The protein is present in all
tissues but highly expressed in nervous tissue, where it is involved in neurogenesis and neuronal
migration, and seems to have pro-survival roles in neurons.
18
UBR4 deficient mice die during
midgestation with multiple developmental anomalies.
19
In humans UBR4 has been suggested to be a
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