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BioMed Research International

Volume 2021, Article ID 6661860, 7 pages
https://doi.org/10.1155/2021/6661860

Research Article
A Novel Missense Variant in the Gene PPP2R5D Causes a Rare
Neurodevelopmental Disorder with Increased Phenotype

Lulu Yan,1 Ru Shen ,2 Zongfu Cao,3 Chunxiao Han,1 Yuxin Zhang,1 Yingwen Liu,1
Xiangchun Yang,1 Min Xie,1 and Haibo Li 1
1
The Central Laboratory of Birth Defects Prevention and Control, Ningbo Women and Children’s Hospital, Ningbo,
Zhejiang 315012, China
2
Department of Laboratory Medicine of Kunming Children’s Hospital, Key Laboratory of Child Critical Disease Research of
Yunnan Province, Kunming, Yunnan 650034, China
3
National Centre for Human Genetic Resource, National Research Institute for Family Planning, Beijing 100081, China

Correspondence should be addressed to Haibo Li; lihaibo-775@163.com

Received 7 December 2020; Revised 1 January 2021; Accepted 1 February 2021; Published 12 February 2021

Academic Editor: Min Tang

Copyright © 2021 Lulu Yan et al. This is an open access article distributed under the Creative Commons Attribution License, which
permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PPP2R5D-related neurodevelopmental disorder, which is mainly caused by de novo missense variants in the PPP2R5D gene, is a
rare autosomal dominant genetic disorder with about 100 patients and a total of thirteen pathogenic variants known to exist
globally so far. Here, we present a 24-month-old Chinese boy with developmental delay and other common clinical
characteristics of PPP2R5D-related neurodevelopmental disorder including hypotonia, macrocephaly, intellectual disability,
speech impairment, and behavioral abnormality. Trio-whole exome sequencing (WES) and Sanger sequencing were performed
to identify the causal gene variant. The pathogenicity of the variant was evaluated using bioinformatics tools. We identified a
novel pathogenic variant in the PPP2R5D gene (c.620G>T, p.Trp207Leu). The variant is located in the variant hotspot region of
this gene and is predicted to cause PPP2R5D protein dysfunction due to an increase in local hydrophobicity and unstable three-
dimensional structure. We report a novel pathogenic variant of PPP2R5D associated with PPP2R5D-related neurodevelopmental
disorder from a Chinese family. Our findings expanded the phenotypic and mutational spectrum of PPP2R5D-related
neurodevelopmental disorder.

1. Introduction PPP2R5D is a member of the phosphatase-2A (PP2A)

Neurodevelopmental disorders (NDDs) are a group of
neurological diseases including intellectual disability (ID),
autism spectrum disorders (ASDs), and language disorders
with common clinical presentations that can affect cognitive,
social, and motor abilities [1, 2]. NDDs have a strong genetic
component, but the specific genetic factors underlying these
disorders are heterogeneous and remain undefined for a large
proportion of affected individuals [3]. With the development
of sequencing techniques, numerous pathogenic genes have
been identified in patients with NDDs [4]. Recently, whole
exome sequencing (WES) has evolved as an effective strategy
to discover and characterize causal variants for a significant
portion of NDD patients [5].
family of phosphatases with critical roles in development,
including maintaining neurons and regulating neuronal sig-
naling. The PPP2R5D gene is located at chromosome 6p21.1,
encoding the B56δ regulatory subunit of PP2A, an intracel-
lular serine/threonine phosphatase. Variants in PPP2R5D
are associated with mild to severe global developmental
delay, hypotonia, ID, ASD, and behavioral abnormalities.
Among these, pronounced hypotonia with delay in gross
motor skills is the most frequently occurring symptom of
PPP2R5D-related neurodevelopmental disorder [6–9]. Ever
since PPP2R5D-related NDD was identified by Del-Mazo
in 1996, more than 100 individuals with PPP2R5D-related
NDD have been described. The disorder has a relatively lim-
ited mutational spectrum with thirteen pathogenic variants
2 BioMed Research International
reported so far [10]. Here, we report a novel pathogenic
variant in exon 5 of the PPP2R5D gene (c.620G>T,
p.Trp207Leu) identified through trio-WES in a Chinese
patient who presented hypotonia, macrocephaly, intellectual
disability, speech impairment, and behavioral abnormalities.
Meanwhile, some new significant clinical phenotypes possi-
bly related to the PPP2R5D variants were also found.
2. Materials and Methods
2.1. The Patient General Information and Ethics Statement.
Ethical approvals for the study were obtained from the
Ningbo Women and Children’s Hospital. Clinical informa-
tion and blood specimens were obtained from the proband
and related family members. The proband underwent thor-
ough examination, including the physical growth and the
behavior development assessment, MRI examination, labora-
tory examination, and EEG measurement. Written informed
consent was provided by the proband’s parents. The proband
was born to nonconsanguineous parents after an uncompli-
cated pregnancy and delivery. Both parents of Chinese origin
and the proband’s brother were unaffected and healthy.
There was no history of any neurodevelopmental abnormal-
ity in the family. The pedigree chart of his family is shown in
Figure 1(a). The proband showed mild developmental delay
(developmental quotient was 69.71), hypotonia, macroce-
phaly (head occipital frontal circumference was 47 cm > 2
SD), prominent forehead, and open mouth at 10 months of
age (Figures 1(b) and 1(c)). He also had a rash because of an
allergy to egg whites, milk, and crabs (Figures 1(d)–1(f)). All
routine laboratory tests revealed normal findings, including
those of blood routine examination, serum biochemical indi-
ces, and amino acid metabolic levels. The electroencephalo-
grams were normal. Magnetic resonance imaging (MRI)
revealed dysgenesis of the corpus callosum, a reduction in
brain parenchyma, widening of the cerebral sulci and
fissures, and enlargement of the ventricular system at 10
months of age. The cerebral structures improved visibly
when reexamined at 24 months of age (Figures 1(g)–1(l)).
Other symptoms included delayed walking, speech impair-
ment, and behavioral issues such as tantrums and trouble
adjusting to new situations. The proband began speaking
“mom” and “dad” at the age of 22 months and walking at
the age of 23 months after rehabilitation.
2.2. DNA Extraction and Whole Exome Sequencing. Genomic
DNA was extracted from peripheral blood leukocytes with
informed consent and hospital ethical approval, using a
QIAamp DNA Blood Mini Kit (Qiagen, Valencia, CA,
USA), according to the manufacturer’s protocol. DNA sam-
ples from the proband and his parents were subjected to
WES using a HiSeq 2500 sequencing platform (Illumina,
San Diego, CA, USA). The low-quality reads were filtered
out from all sequencing data using a quality score 20 (Q20);
the filtered sequencing data were compared to the human
reference genome (hg19) using BWA. Then, variants were
called by GATK and annotated to public databases by Anno-
var. The minor allele frequencies (MAFs) of all known vari-
ants were also reported according to their presence in the
dbSNP 1000 Genomes Project (1000 GP), Exome Aggrega-
tion Consortium, and Exome Variant Server databases. Data-
bases such as OMIM, ClinVar, HGMD, and SwissVar were
used to determine mutation harmfulness and pathogenicity
where appropriate. All whole-exome variants were subjected
to biological effect analysis, which included the use of pro-
grams such as SIFT, MutationTaster, PolyPhen-2, PRO-
VEAN, Human Splicing Finder, and MaxEntScan to predict
whether an amino acid substitution or indel has an important
biological effect. Variants were selected after combining the
clinical information and then classified as pathogenic, likely
pathogenic, variant of uncertain significance, likely benign,
or benign according to the American College of Medical
Genetics and Genomics (ACMG) guidelines.
2.3. Validating by Sanger Sequencing. To validate the variant
screened by WES, Sanger sequencing was performed for the
proband and family members. Genomic DNA was amplified
by PCR using the PCR primers (forward, 5 ′ -TGTCCTCTT
TGACTTCGTG-3 ′ ; reverse, 5 ′ -TTCTTGGCTATGTTTG
GC-3 ′ ), which were designed with Primer 5 software. PCR
conditions were as follows: 94°C for 10 min of initial dena-
turation followed by 30 cycles of amplification of 30 s at
94°C, 30 s at 60°C, and 45 s at 72°C. After reacting with Big-
Dye Terminator v3.1, the PCR products were run on an ABI
3500DX Genetic Analyzer (Applied Biosystems, Foster City,
CA) and analyzed by Sequencing Analysis Software 6. After
validating the variant, family segregation was performed for
all individuals.
2.4. Bioinformatics Analysis and Pathogenicity Assessment.
The PPP2R5D protein sequence was obtained from the NCBI
Protein Database (https://www.ncbi.nlm.nih.gov/protein/) in
FASTA format. Online tools PolyPhen-2, SIFT, MutationTa-
ster, and PROVEAN were used to predict the pathogenicity
of the missense variant. Multiple sequence alignment and
conservative analyses were performed using MEGA software.
The hydrophobic properties of wild-type and mutant
PPP2R5D protein were analyzed by ProtScale (https://web
.expasy.org/protscale/). The 3D structures of wild-type and
mutant protein were generated using the I-TASSER online
server and PyMOL tool (http://zhanglab.ccmb.med.umich
.edu/I-TASSER/, http://www.pymol.org/). The variant path-
ogenicity was assessed in standards and guidelines recom-
mended by the American College of Medical Genetics and
Genomics and the Association for Molecular Pathology
(ACMG/AMP) [11].
3. Results
Trio-WES revealed 13 variants (Table 1) after filtering,
among which PPP2R5D carried a de novo heterozygous var-
iant (c.620G>T/p. Trp207Leu) (Figure 2(a)). The variant is
located at a known variant hotspot (p. Trp207) within the
B56 domain of this protein. The tryptophan at position 207
was highly conserved in different species (Figure 2(b)). By
ProtScale analysis, it was found that the hydrophobicity of
the protein increased because of the altered amino acid.
Therefore, the change of this amino acid could generate
BioMed Research International 3

I
1 2

II

1 2

(a) (b) (c)

(d) (e) (f)

(g) (h) (i)

(j) (k) (l)

Figure 1: A Chinese boy presents NDD. (a) Family pedigree. Arrow indicates the proband (II2); squares indicate males; circles indicate females;
the filled symbol indicates the affected individual. (b–f) Facial and skin features of the patient at 10/19 months of age. (b, c) The patient displays
macrocephaly, prominent forehead, and open mouth. (d–f) Allergic rash. Mainly concentrated on the limbs and trunk. (g–l) Brain MRI of the
proband. (g–i) MRI showed a hypoplastic corpus callosum, temporal lobe parenchymal atrophy, enlargement of the ventricular system, and
retardation of myelination of the white matter. (j–l) The bilateral temporal cortex was clear and plump (red arrows).

alterations in the protein structure (Figure 2(c)). Further-
more, according to the I-TASSER tool prediction, there was
a significant difference in the tertiary structural features
between the wild-type and mutant PPP2R5D proteins. The
Trp207Leu substitution impacted the formation of hydrogen
bonds. Trp207 interacted with the Glu204 and Gln211 resi-
dues through hydrogen bonds, whereas the more hydropho-
bic residue leucine resulted in altered hydrogen bonding with
Glu204 and Gln211 (Figures 3(a) and 3(b)). The amino acid
replacement is not observed in unaffected family members
and is absent from control databases, as well as 200 local con-
trols. The majority of variant pathogenicity prediction tools
supported the disease-causing consequence of this novel mis-
sense variant including a REVEL score of 0.7979. The variant
is classified as pathogenic following the ACMG/AMP guide-
lines (PS2, PM1, PM2, PM5, PP2, and PP3) [8].
4. Discussion
PPP2R5D-related NDD is a recently characterized disorder.
It is also known as Jordan’s syndrome, named after Jordan
Lang, the first child diagnosed in the United States. Since
 4
Table 1: 13 variants in whole exome sequencing that were remaining after bioinformatic filtering.

Nucleotide Amino acid Chromosome

Gene Inheritance Transcript Exon/intron Type Disease’s name (OMIM) Proband Father Mother
alteration alteration position
chr6:429 Nonsynonymous Mental retardation,
PPP2R5D [1]/[2]AD NM_006245.3 Exon5 c.620G>T p.W207L Het / /
75031 SNV autosomal dominant 35
chr16:3778291- Menke-Hennekam syndrome
c.6746_ p.R2249_Q2 Nonframeshift
CREBBP [1]/[2]AD NM_004380.2 Exon31 3778302:GCTGC 1; Rubinstein-Taybi Het Het /
6757 del 252del deletion
TGCATGC:- syndrome 1
Hypogonadotropic
Nonsynonymous
PROKR2 [1]AD NM_144773.3 Exon3 c.889G>A p.V297I chr20:5282952:C:T hypogonadism 3 with Het Het /
SNV
or without anosmia
Spinocerebellar ataxia,
autosomal recessive 24;
chr3:132394712: Nonsynonymous
UBA5 [1]AR NM_024818.4 Exon11 c.1076G>A p.G359D epileptic encephalopathy, Het / Het
G:A SNV
early infantile,
44
1]AR chr10:27431366: Nonsynonymous
YME1L1 NM_139312.2 Exon5 c.551A>T p.H184L Optic atrophy 11 Het Het /
[2]AR T:A SNV
Infantile liver failure syndrome
[1]AR Nonsynonymous 2; short stature, optic nerve
NBAS NM_015909.3 Exon34 c.3938C>T p.P1313L chr2:15493828:G: A Het Het /
[2]AR SNV atrophy, and Pelger-Huet
anomaly
Nonsynonymous
ARL13B [1]AR NM_182896.2 Exon2 c.106G>A p.A36T chr3:93714764:G:A Joubert syndrome 8 Het Het /
SNV
Nonsynonymous Mental retardation,
ANK3 [1]AR NM_020987.4 Exon37 c.6832A>C p.K2278Q chr10:61833807:T:G Het Het /
SNV autosomal recessive, 37
Nonsynonymous Methylmalonyl-CoA
MCEE [1]AR NM_032601.3 Exon2 c.275G>A p.G92E chr2:71351439:C:T Het / Het
SNV epimerase deficiency
Nonsynonymous Beta-ureidopropionase
UPB1 [1]AR NM_016327.2 Exon2 c.142T>C p.S48P chr22:24896112:T:C Het Het /
SNV deficiency
Ehlers-Danlos syndrome,
[1]AD Nonsynonymous vascular type; polymicrogyria
COL3A1 NM_000090.3 Exon21 c.1472G>A p.R491Q chr2:189859788:G:A Het / Het
[2]AR SNV with or without vascular-type
EDS
Cataract 41; deafness, autosomal
[1]AD dominant 6/14/38; Wolfram
[2]AD syndrome 1; Wolfram-like
Nonsynonymous
WFS1 [3]AR NM_006005.3 Exon4 c.400G>A p.A134T chr4:6290798:G: A syndrome, 54,46,autosomal Het Het /
SNV
[4]AD dominant; diabetes mellitus,
[5]AD noninsulin-dependent,
association with
[1]AR Nonsynonymous Roberts syndrome; SC
ESCO2 NM_001017420.2 Exon3 c.694C>T p.R232C chr8:27634519:C:T Het / Het
[2]AR SNV phocomelia syndrome
AD: autosomal dominant; AR: autosomal recessive; Het: heterozygous; Hom: homozygous; SNV: single nucleotide variants.
BioMed Research International
BioMed Research International 5

Father Mother Proband:c.620G>T(p.Trp207Leu)

G A AG C T G C T T G G C C A CA T C T G A AG C T G C T T G G C C A C A T C T G A AG C T G C T T G G C C A C A T C T

(a)

Human D E P T L E A A W P H L Q L V Y E
Mouse D E P T L E A A W P H L Q L V Y E
Rat D E P T L E A A W P H L Q L V Y E
Zebrafish D E P T L E A A W P H L Q L V Y E
Monkey D E P T L E A A W P H L Q L V Y E
Chimpanzee D E P T L E A A W P H L Q L V Y E
Cattle D E P T L E A A W P H L Q L V Y E
Dog D E P T L E A A W P H L Q L V Y E
Chicken D E P T L E A A W P H L Q L V Y E
Pig D E P T L E A A W P H L Q L V Y E
Horse D E P T L E A A W P H L Q L V Y E
(b)
3

2
Hydrophobicity score

1
0.356
0

–1
-0.167
–2

–3
–4
0 200 400 600
Position
WT
Trp207Leu
(c)
c.589G>A
c.592G>A
c.598G>A
c.602C>G
c.619T>A
c.619T>C c.752A>C
c.620G>T c.752A>T
PPP 2R5D gene c.157C>T c.253C>T c.632A>C c.758G>C c.1258G>A

5’UTR 3’UTR

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

(d)

Figure 2: Identification of a missense variant in the PPP2R5D gene. (a) The novel heterozygous variant c.620G>T (p.Trp207Leu) in PPP2R5D
was verified by Sanger sequencing. The variant is marked by a red arrow. (b) Protein alignment shows that the 207th tryptophan (marked by a
red arrow) is highly conserved among different species. (c) Hydrophobicity of PPP2R5D protein. The prediction by ProtScale indicates an
increase of local hydrophobicity around the site of p.Trp207Leu variant. WT: wild type. (d) The schematic diagram showing the gene
structure of PPP2R5D. The variant in PPP2R5D occurs in exon 5, which causes G to T substitution at nucleotide 620 (NM_006245.3).
Previously reported pathogenic variants are marked in black, and the variant identified in this study is highlighted in red.

then, more than 100 cases have been identified across the tonia (73.91%), ophthalmologic abnormalities (38.89%), and
globe [10]. The clinical manifestations of individuals with seizures (26.09%) [12].
PPP2R5D variants included developmental delay and/or To the best of our knowledge, only two Chinese patients
intellectual disability (100%), macrocephaly (78.26%), hypo- with macrocephaly and NDDs have been reported with the
6 BioMed Research International
GLU-204
GLN-211
TRP-207
(a)
Figure 3: Structural modeling of PPP2R5D protein. The I-TASSER tool predicts the structural changes caused by the p.Trp207Leu variant.
(a) Amino acid at position 207 of wild-type PPP2R5D protein interacted with the Glu204 and Gln211 residues through hydrogen bonds
which are presented as yellow dashed lines. (b) The formation of hydrogen bonds is predictably altered by the substitution of tryptophan
by leucine at position 207.
same heterozygous missense variant (c.G592>A) of the
PPP2R5D gene [13]. We reported a third Chinese patient with
a novel pathogenic variant c.620G>T (p.Trp207Leu). Both
two Chinese patients diagnosed previously had similar pheno-
types comparable to other patients with PPP2R5D variants,
including moderate global developmental delay, mild ID,
frontal bossing, hypertelorism, and a history of epilepsy [13].
Some phenotypes of our patient are highly consistent with
other PPP2R5D-related NDD patients, such as the specific
feature of macrocephaly, prominent forehead, hypotonia,
delayed speech and language development, and mild ID. In
terms of nonspecific brain MRI results, the overall brain
development of our patient was slower than that of other
children of the same age. In addition to the aforementioned
clinical manifestations, our patient also exhibited a serious
allergic rash of the skin, which has not been described in pre-
vious cases. It is not clear whether this clinical manifestation
is part of the symptomatology of PPP2R5D-related NDD,
and it could possibly represent a new clinical phenotype.
PP2A complex is a heterodimeric core enzyme, which is
composed of a scaffolding subunit A, a regulatory subunit
B, and a catalytic subunit C [14]. B56δ is one of the isoforms
of subunit B and is highly expressed in the human brain [15].
There is evidence that PP2A-PPP2R5D holoenzyme is
involved in controlling the activity of the PI3K/AKT signal-
ing pathway that plays a role in the maintenance and func-
tioning of neurons [8]. According to the previous report, all
ID-associated PPP2R5D variants except Pro53Ser resulted
in deficient holoenzyme formation, most likely through a
dominant-negative mechanism [7].
To date, a limited variant spectrum of PPP2R5D involv-
ing 12 missense variants and 1 nonsense variant has been
identified (https://www.ncbi.nlm.nih.gov/clinvar/), and most
of the PPP2R5D variants are located in exon 5 (Figure 2(d)).
Among these variants, the Trp207Arg pathogenic variant is
positioned in a conserved acidic loop of the PPP2R5D
GLU-204
LEU-207
GLN-211
(b)
subunit critical for PP2A-PPP2R5D holoenzyme formation.
The patient with the Trp207Arg variant learned to walk at
the age of 2. In addition to moderate ID, developmental
delay, hypotonia, and macrocephaly, he(she) also had scolio-
sis, hip dysplasia, and fatigue [7]. In the present study, a de
novo missense variant c.620G>T (p.Trp207Leu) in exon 5
of the PPP2R5D gene was successfully identified in a Chinese
patient with PPP2R5D-related NDD. The Trp207 amino acid
in PPP2R5D is highly conserved among 10 species based on
sequence alignment. Analyses by all the variant pathogenicity
prediction tools supported the disease-causing consequence
of this novel missense variant. In addition, the Trp207Leu
substitution impacts the formation of hydrogen bonds of
the Trp207 with the Glu204 and Gln211 residues and is pre-
dicted to increase the local hydrophobicity and disrupt the
PPP2R5D protein structure/function. We therefore con-
cluded that the Trp207Leu variant in PPP2R5D was the
genetic etiology underlying PPP2R5D-related NDD in the
proband. The research by Houge et al. [7] demonstrated
deficient holoenzyme formation of PP2A due to decreased
association of the mutant PPP2R5D subunit to the subunit
A or subunit C. The Trp207Leu variant in the PPP2R5D gene
may similarly perturb interactions between subunits of the
PP2A complex [16]. Further functional studies will be
focused on this rare variant site for deeper understanding
of its functional implications.
In conclusion, a de novo PPP2R5D variant was identified
in a Chinese patient with NDD through WES, which
expanded the mutational and phenotypic spectrum of
PPP2R5D-related NDD. There are no known effective treat-
ments for NDDs associated with PPP2R5D variants. How-
ever, early intervention and rehabilitation therapy are
available, which helped our patient to regain some impaired
abilities. Further studies are required to assess the impact of
PPP2R5D variants on neuronal functions and to facilitate
the development of novel therapeutic strategies.
BioMed Research International 7

Data Availability lectual disability,” Journal of Clinical Investigation, vol. 125,

no. 8, pp. 3051–3062, 2015.
The data used to support the findings of this study are [8] C. Loveday, K. Tatton-Brown, M. Clarke et al., “Mutations in
included within the article. the PP2A regulatory subunit B family genes PPP2R5B,
PPP2R5C and PPP2R5D cause human overgrowth,” Human
Conflicts of Interest Molecular Genetics, vol. 24, no. 17, pp. 4775–4779, 2015.
[9] L. Shang, L. B. Henderson, M. T. Cho et al., “De novo missense
The authors declare that there are no competing interests variants in PPP2R5D are associated with intellectual disability,
associated with the manuscript. macrocephaly, hypotonia, and autism,” Neurogenetics, vol. 17,
no. 1, pp. 43–49, 2016.
Authors’ Contributions [10] “Jordan’s Guardian Angels,” https://jordansguardianangels
.org/the-history-of-jordans-syndrome/. Accessed on 10 Feb-
Haibo Li, Lulu Yan, and Ru Shen conceived and designed the ruary 2020.
study. Zongfu Cao, Yuxin Zhang, Yingwen Liu, and Chun- [11] S. Richards, N. Aziz, S. Bale et al., “Standards and guidelines
xiao Han conducted the experiments and data analysis. for the interpretation of sequence variants: a joint consensus
Xiangchun Yang and Min Xie collected tissue samples. All recommendation of the American College of Medical Genetics
authors read and approved the final manuscript. Lulu Yan and Genomics and the Association for Molecular Pathology,”
and Ru Shen are co-first authors. Lulu Yan and Ru Shen con- Genetics in Medicine, vol. 17, no. 5, pp. 405–423, 2015.
tributed equally to this work. [12] G. Mirzaa, K. Foss, M. Nattakom, and W. K. Chung,
“PPP2R5D-related neurodevelopmental disorder,” GeneRe-
views®, pp. 1993–2020, 2019.
Acknowledgments [13] K. S. Yeung, W. Tso, J. Ip et al., “Identification of mutations in
the PI3K-AKT-mTOR signalling pathway in patients with
We are grateful to Dr. Jiong Gao (BGI Genomics, BGI-
macrocephaly and developmental delay and/or autism,”
Shenzhen 518083, China) for assisting in bioinformatics Molecular Autism, vol. 8, no. 1, p. 66, 2017.
analysis. We would like to thank the proband’s family for
[14] V. Janssens, J. Goris, and C. Van Hoof, “PP2A: the expected
their cooperation and interest to participate in this study.
tumor suppressor,” Current Opinion in Genetics & Develop-
We also acknowledge the National Population and Repro- ment, vol. 15, no. 1, pp. 34–41, 2005.
ductive Health Science Data Center, People’s Republic of
[15] M. Uhlen, L. Fagerberg, B. M. Hallstrom et al., “Tissue-based
China (Grant No. 2005DKA32408), the Medical and Health
map of the human proteome,” Science, vol. 347, no. 6220, arti-
Project of Zhejiang Province (Grant No. 2020KY890), and cle 1260419, 2015.
the Social Development Public Welfare Foundation of
[16] Deciphering Developmental Disorders Study, “Large-scale dis-
Ningbo (Grant No. 202002N3150 and 2019C50070). covery of novel genetic causes of developmental disorders,”
Nature, vol. 519, no. 7542, pp. 223–228, 2015.
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