Interstitial microduplication at 2p11.2 in a patient with syndromic intellectual disability: 30-year follow-up
© Jun et al.; licensee BioMed Central Ltd. 2014
Received: 8 May 2014
Accepted: 20 June 2014
Published: 19 August 2014
Copy number variations at 2p11.2 have been rare and to our knowledge, no abnormal phenotype with an interstitial 2p11.2 duplication has yet been reported. Here we report the first case with syndromic intellectual disability associated with microduplication at 2p11.2.
We revisited a white female subject with a chromosome translocation, t(8;10)(p23;q23)mat and a 10q telomeric deletion suspected by G-banding 30 years ago. This female with severe intellectual disability, no speech, facial dysmorphism, intractable epilepsy, recurrent infection, and skeletal abnormalities has been observed from the birth until her death. The karyotype analysis reconfirmed the previously reported chromosome translocation with a revision as 46,XX,t(8;10)(p23.3;q23.2)mat by adding more detail in chromosomal sub-bands. The array comparative genomic hybridization, however, did not detect the 10q terminal deletion originally reported, but instead, revealed a 390 kb duplication at 2p11.2; 46,XX,t(8;10)(p23.3;q23.2)mat.arr[hg 19] 2p11.2(85469151x2,85474356-85864257x3,85868355x2). This duplication region was confirmed by real-time quantitative PCR and real-time reverse transcriptase quantitative PCR.
We suggest three positional candidate genes for intellectual disability and recurrent infection based upon gene function and data from real-time reverse transcriptase quantitative PCR—VAMP8 and RNF181 for intellectual disability and CAPG for recurrent infection.
KeywordsArray CGH CAPG Copy number variation Duplication Intellectual disability Recurrent infection RNF181 2p11.2 VAMP8
A variety of terminal 2p duplications known as partial 2p trisomy are the unbalanced chromosomal rearrangements resulting from malsegregation of various balanced translocations [1–3]. Interpretation of the clinical phenotypes of carriers with these unbalanced translocations is complicated due to the co-existence of terminal monosomy and terminal trisomy. Different isolated duplications within the 2p region had been reported in more than 20 patients, but they vary in size and location, ranging from 2p12 to 2p25 [4–7]. These duplications are associated with a syndromic phenotype including intellectual disability, growth and psychomotor retardation, delayed bone age, congenital heart abnormalities, pulmonary hypoplasia, hypoplastic kidney, genital anomaly, anencephaly, neural tube defects, finger and toe abnormalities, or dysmorphic facial features encompassing hypertelorism, prominent forehead, broad nasal bridge, low-set ear, and micrognathia [4–7]. Because the size and location of these 2p duplications may vary from individual to individual, comparison of overlapping regions for defining a minimal candidate region associated with a particular phenotype will be a useful strategy for identifying the causative gene as exemplified in the mapping of deletions [8, 9].
Due to the limited resolution of banding and staining patterns of chromosomes in the pre-FISH (FISH-fluorescent in situ hybridization) and pre-CGH (CGH-comparative genomic hybridization) era, it is not uncommon to find misinterpretations of cytogenetic aberrations in the reported cases, which complicated attempts to assign a unique phenotype to a specific chromosome band. Here we revisited a case reported 30 years ago  and failed to confirm an ostensible 10q deletion. Instead, we identified a cryptic 2p11.2 microduplication by a microarray in the affected female subject. Some of her clinical features were developed years later in her life. To our knowledge, this is the first case with syndromic intellectual disability associated with an interstitial 2p11.2 duplication. Genotype/phenotype relationships have been discussed.
Clinical report in a 30 year time period
The patient is a 30 year old white female with severe intellectual disability, a severe static encephalopathy, medically intractable epilepsy, and facial dysmorphism. She was first evaluated at the age of 10 months because of gastroenteritis and middle ear infection . At that time, her height, weight and head circumference were in the 3rd percentile for chronological age. She is the first living child of healthy non-consanguineous marriage. The father was 42 years old and the mother with a previous spontaneous abortion was 26 years old at the birth of their daughter. Prenatal screening demonstrated normal alpha-fetoprotein levels for gestational age and a normal ultrasound, but studies indicated an Rh-sensitized status. The subject was a 2,700 g female at 35 weeks of gestation born by cesarean section.
The detection of microduplication at 2p11.2
Based on the aberrant karyotype and array CGH result found in the patient, the nomenclature is revised as 46,XX,t(8;10)(p23.3;q23.2)mat.arr[hg 19] 2p11.2(85469151x2,85474356-85864257x3,85868355x2).
The confirmation of duplicated region by real-time quantitative PCR
Primers used for qPCR, qRT-PCR, and RT-PCR
Gene name (GenBank accession number)
Primer sequence (5′ → 3′)
primer pair #1F
primer pair #1R
primer pair #2F
primer pair #2R
primer pair #3F
primer pair #3R
primer pair #1F
primer pair #1R
primer pair #2F
primer pair #2R
primer pair #4F
primer pair #4R
primer pair #5F
primer pair #5R
Genes located at the duplicated region of 2p11.2
Transcription factor 7-like 1 (T-cell specific, HMG-box)
Transcription factor 7-like 1 (a member of T cell factor/lymphoid enhancer factor family of transcription factors)
Mediation of Wnt signaling pathway, regulation of cell cycle genes and cellular senescence
Homozygous mutant mice exhibit severe embryological defects particularly affecting the cardiovascular system, nervous system, and digestive system.
Not affected by our duplication based on qRT-PCR result.
Trans-golgi network protein 2
Trans-Golgi network integral membrane protein 2 precursor
Exocytic vesicle formation
No knock-out mice. A 7.8 kb deletion involving all 4 exons within the gene was reported in a normal control person.
All-trans-retinol 13,14-reductase precursor
All-trans-retinol 13,14-reductase activity, oxidoreductase activity
No knock-out mice.
ELMO/CED-12 domain containing 3
ELMO domain-containing protein 3, isoform a, b,
Phagocytosis and cell migration
Deafness, autosomal recessive 88 (OMIM 615429)
No knock-out mice.
Capping protein (actin filament), gelsolin-like
Control of actin-based motility in non-muscle cells
Inactivation of this loci results in impaired immune cell motility which manifests in homozygous mutant mice as increased susceptibility to some bacterial infections.
SH2 domain containing 6
SH2 domain-containing protein 6
No knock-out mice.
Uncharacterized non-coding RNA
No knock-out mice.
Methionine adenosyltransferase II, alpha
Production of S-adenosylmethionine from methionine and ATP
No knock-out mice. A 28 kb duplication containing this gene and GGCX was reported in a normal control person.
Vitamin K-dependent gamma-carboxylase
Posttranslational modification of vitamin K-dependent protein
Autosomal recessive pseudoxanthoma elasticum-like disorder with multiple coagulation factor deficiency (OMIM 610842)
Only 50% of expected Ggcx(-/-) mice survive to term but the latter animals die uniformly at birth of massive intra-abdominal hemorrhage. A 28 kb duplication containing this gene and TAT2A was reported in a normal control person.
Autosomal recessive vitamin K-dependent coagulation defect (OMIM 277450)
Vesicle-associated membrane protein 8
Vesicle-associated membrane protein 8
Fusion of synaptic vesicles with the presynaptic membrane
Homozygous knock-out mice exhibit background-sensitive postnatal lethality, hydronephrosis, and reduced amylase secretion, type I hypersensitivity reaction, and platelet activation.
Vesicle-associated membrane protein 5
Vesicle-associated membrane protein 5
Docking and/or fusion of vesicles and cell membranes
No knock-out mice.
Ring finger protein 181
E3 ubiquitin-protein ligase RNF181
E3 ubiquitin ligase activity
No knock-out mice. A 36 kb deletion encompassing the whole gene was reported in a normal control person.
Transmembrane protein 150A
Transmembrane protein 150A precursor
No knock-out mice.
Chromosome 2 open reading frame 68
UPF0561 protein C2orf68
No knock-out mice.
Ubiquitin specific peptidase 39
U4/U6.U5 tri-snRNP-associated protein 2
Ubiquitin thiolesterase activity, zinc ion binding
No knock-out mice.
A 12 kb deletion encompassing exons 4–6 and a 5.6 kb deletion encompassing exons 7–9 was reported in normal control persons.
Not affected by our duplication based on qRT-PCR result.
Among the genes duplicated, the following CNVs have been identified in healthy control persons, thereby potentially ruling out them as candidate genes if gene dosage effect is underlying mechanism: a 7.8 kb deletion involving all 4 exons within the gene TGOLN2, a 28 kb duplication containing two genes, MAT2A and GGCX, a 36 kb deletion encompassing whole gene RNF181, and a 12 kb deletion encompassing exons 4–6  and a 5.6 kb deletion encompassing exons 7–9  of the gene USP39 (Table 2).
Interstitial deletions encompassing 2p11.2 are particularly rare, with only seven cases reported to date [16, 17]. Among them, the interstitial deletion of 2p11.2-2p12 was confirmed in only three cases by array CGH , high-resolution CGH , or qPCR . These deletions ranged in size from 7.5 to 11.4 Mb, encompassing the 390 kb duplicated region of our case. The patient with an 11.4 Mb deletion had psychomotor retardation, mild cutaneous syndactylies, pectus carinatum, hyperlordosis, clubfeet, single umbilical artery, and facial abnormalities, such as low-set ears, broad nasal bridge, frontal bossing, and dolichocephaly . In family 3, a son with a 7.5 Mb deletion presented with impairment of physical development, and intellectual disability, language delay including a pronunciation problem, suspected epilepsy, recurrent Wilms tumor, a large head with frontal bossing, a flat face, and low-set abnormally molded ears . His mother with the same deletion had features similar to her son, such as abnormally molded ears, a severe pronunciation problem, and intellectual disability .
Two obstacles hampered us to compare the overlapping phenotype and genomic regions between our duplication patient and three patients with deletions encompassing 2p11.2. Firstly, we do not know whether a dosage effect of genes is involved in both deletions and our duplication, and whether increased or decreased gene dosage would give rise to the same phenotype. Secondly, the genomic regions of 7 reported deletion cases are so large that they could contain more than one gene for a specific phenotype such as intellectual disability. In this circumstance, the simple comparison of overlapping regions in two groups of inappropriately different sized CNVs is not meaningful because our duplication is only 390 kb and the smallest deletion among 7 deletion cases is 7.5 Mb containing a large number of genes.
Therefore, we analyzed known and deduced functions of genes within the duplicated region. While the chromosome band 2p11.2 of 7.2 Mb contains many genes, fifteen annotated genes are located in 390 kb duplicated region of our case; TCF7L1, TGOLN2, RETSAT, ELMOD3, CAPG, SH2D6, LOC100630918, MAT2A, GGCX, VAMP8, VAMP5, RNF181, TMEM150A, C2orf68, and USP39 (Figure 3A, Table 2). These are all protein-coding genes, except the non-coding RNA LOC100630918.
The multisystemic disorder in our patient suggests that it is caused by more than one gene or by a single gene encoding a transcription factor regulating various target genes. Among the genes in the duplicated region, TCF7L1 (transcription factor 7-like 1, formerly named TCF3, MIM 604652) is a mediator of the WNT signaling pathway . This gene encodes a transcription factor, which is a member of the T-cell factor/lymphoid enhancer factor. Importantly, TCF7L1 physically interacts with CTNNB1 [catenin (cadherin-associated protein), beta 1, MIM 116806] , mutations of which cause severe intellectual disability with absent or very limited speech, microcephaly, and spasticity . Since proteins accomplish most of their functions by interacting with other molecules, we wondered whether TCF7L1 might be involved in intellectual disability by increasing gene dosage from the duplication. Theoretically, TCF7L1 at the distal duplication junction would express one intact and one truncated transcript, respectively (Figure 4). The truncated one with 3′ end is most likely not expressed due to the lack of the promotor and putative start codon. This was confirmed by qRT-PCR with two different primer pairs—#1 and #2 designed from the 5′ end and 3′ end of this gene (Figures 3A and 4, Table 1), which failed to demonstrate any change in expression in the patient, her healthy mother, and sister (data not shown). This finding makes it highly unlikely that TCF7L1 is a candidate for intellectual disability.
The gene USP39 (ubiquitin specific peptidase 39, MIM 611594) is also a good candidate for intellectual disability since alterations of the ubiquitin/proteasome system (UPS) may engender neuronal dysfunction leading to neurological disease and intellectual disability . This gene truncated at the proximal duplication junction would consequently be predicted to produce one intact and one truncated transcript with the 5′ end (Figure 4). Two primer pairs #4 and #5 were designed from the 5′ end and 3′ end of this gene, respectively, for qRT-PCR (Figure 4 and Table 1). The amount of transcript (from two different regions) was not different in the patient, her unaffected mother, and sister (data not shown), suggesting that this gene is not affected by the duplication.
Since the transcription of two truncated genes, TCF7L1 and USP39, is in the same direction, there is a possibility of producing a fusion gene (Figure 4). Practically, it is unlikely that the fusion gene is expressed. If it had been expressed, the amplicon from primer pair #2 would have shown overexpression due to additional expression from the second half of the fusion gene comprising of partial TCF7L1 with the 3′ end (Figure 4). This hypothesis that the fusion gene was not expressed is confirmed because RT-PCR failed to demonstrate the presence of the putative fusion gene USP39/TCF7L1 (data not shown), using a forward primer from USP39 and a reverse primer from TCF7L1, (Figure 4 and Table 1).
After eliminating TCF7L1 and USP39, two partially duplicated but unaffected genes, VAMP8 and RNF181 become plausible candidate genes for intellectual disability seen in our patient among the 13 genes duplicated at 2p11.2. VAMP8 (vesicle-associated membrane protein 8, MIM 603177) encodes a protein involved in the fusion of synaptic vesicles with the presynaptic membrane. It interacts with YWHAE (tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, epsilon polypeptide, MIM 605066) . Heterozygous knock-out mice show neuron migration defects, mild defects in spatial working memory, and possibly enhanced anxiety in an elevated plus-maze test. This phenotype coupled with the genetic association between one SNP in the 5′ flanking region of YWHAE and schizophrenia suggested this gene a possible susceptibility gene for this psychiatric disorder . This makes VAMP8 an attractive candidate gene for intellectual disability. RNF181 (ring finger protein 181, MIM 612490) has E3 ubiquitin ligase activity  and because ubiquitination plays a crucial role in neurodevelopment as aforementioned , this is a good candidate for intellectual disability.
At least, five genes, HUWE1 (MIM 300697), PARK2 (MIM 602544), UBE3A (MIM 601623), UBE3B (MIM 608047), RNF216 (MIM 609948), encoding E3 ubiquitin ligases, have been involved in intellectual disability or another neurological phenotype. Mutations of HUWE1 (HECT, UBA and WWE domain containing 1) are associated with X-linked intellectual disability  and PARK2 (Parkinson protein 2) is mutated in Parkinson patients . Genetic alterations of UBE3A (ubiquitin protein ligase E3A) cause Angelman syndrome characterized by intellectual disability, seizures, frequent smiling and laughter, and abnormal gait . Biallelic loss-of-function mutations of UBE3B (ubiquitin protein ligase E3B) cause autosomal recessive blepharophimosis-ptosis-intellectual-disability syndrome . Inactivating mutations of RNF216 (ring finger protein 216) cause Gordon Holmes syndrome, which is characterized by cerebellar ataxia, dementia, and hypogonadotropic hypogonadism .
Additionally, CUL4B (cullin 4B, MIM 300304) associated with syndromic X-linked intellectual disability is a scaffold subunit of E3 ubiquitin-protein ligase complex  and UBE2A (ubiquitin-conjugating enzyme E2A, MIM 312180) encoding E2 ubiquitin-conjugating enzyme are associated with X-linked intellectual disability . An unaffected individual with a 36 kb deletion encompassing whole gene RNF181 has been reported as aforementioned . However, we still cannot exclude the possibility that overexpression from a duplication, which was confirmed by qRT-PCR (Figure 3F), rather than haploinsufficiency, might cause intellectual disability.
Among the duplicated genes, CAPG [capping protein (actin filament), gelsolin-like, MIM 153615] encodes a macrophage-capping protein, which controls actin-based motility in non-muscle cells. Homozygous mutant mice lacking this gene manifest increased susceptibility to some bacterial infections . This gene might also have had some influence on the patients’ phenotype as a result of the duplication, given that qRT-PCR showed its overexpression in our patient with recurrent fungal infection on the skin of her hands (Figures 1I, J, and 3D). The patient commonly placed her hands into her mouth, biting her fingers with self-injurious behavior. Her skin lesions were sometimes complicated with fungal infections and treated with antifungal cream, clotrimazole.
Lastly, two genes, ELMOD3 and GGCX, involved in recessive disorders were ruled out as candidate genes because of the absence of associated clinical features of these two genes in our patient with a likely autosomal dominant phenotype due to the heterozygous duplication. A homozygous missense mutation of ELMOD3 (ELMO/CED-12 domain containing 3, MIM 615427) was found by whole exome sequencing combined with homozygosity mapping in a Pakistani family with autosomal recessive nonsyndromic deafness-88 (DFNB88, MIM 615429) , while homozygous missense and compound heterozygous mutations of GGCX (gamma-glutamyl carboxylase, MIM 137167) cause vitamin K-dependent coagulation defect (MIM 277450) [34, 35] and pseudoxanthoma elasticum-like Disorder with multiple coagulation factor deficiency (MIM 610842) .
In summary, here we report the first interstitial duplication of 2p11.2 associated with syndromic intellectual disability. Based on the functional characterization and qRT-PCR of the genes, we suggest three positional candidate genes—VAMP8 and RNF181 for intellectual disability and CAPG for recurrent infection. In concert with the qRT-PCR data, we propose increased gene dosage as the underlying mechanism of the two phenotypes.
For high resolution karyotype, peripheral blood lymphocytes from the patient, mother, and younger sister were cultured with Phytohematoagglutinin and harvested for cytogenetic analysis using standard techniques. Chromosome analysis was performed on GTL-banded chromosomes at an approximately 550 band level.
Methylation studies of the 15q11-q13 region was performed with enzymes Hind III and Cfo I and Southern blot analysis with probe PW71B.
DNA copy number variants were investigated using a 400 k whole genome oligonucleotide array (GPL9777) employing the protocols for array CGH provided by the manufacturer (Agilent, Santa Clara, USA). Image analysis, normalization, and annotation were done with Feature Extraction 10.5.1.1 (Agilent, Santa Clara, USA) using the default settings. Data visualization and further analysis was performed with GenomeCAT (http://www.molgen.mpg.de/~abt_rop/molecular_cytogenetics/CGHPRO.html). CNVs were determined by circular binary segmentation .
To confirm the duplicated region, three primer pairs were designed for real-time quantitative PCR (qPCR)—pairs #1 and #2 from the 5′ and 3′ ends of the gene TCF7L1, respectively, and #3 from the gene TMEM150A (Figure 3A, Table 1). Primer pair #1 was designed from the outside of the duplicated region as a negative control, whereas primer pairs #2 and #3 were designed from within the duplicated region (Figure 3A). qPCR was performed using an ABI 7300 Realtime PCR system (Applied Biosystem, Foster City, CA, USA) according to the manufacturer’s instructions (Figure 3C). The copy number was measured relative to GAPDH.
For real-time reverse transcriptase quantitative PCR (qRT-PCR), RNA was extracted from lymphoblastoid cell lines by Trizol Reagent (Invitrogen, Calsbad, CA, USA). Total RNA was reverse-transcribed into cDNA by RevertAid First-strand cDNA synthesis (Thermo Fisher Scientific, Glen Burnie, MA, USA). qRT-PCR for TCF7L1, CAPG, VAMP8, RNF181, and USP39 was performed with SYBR (RT2 SYBR Green, Qiagen, Gaithersburg, MD, USA) on an ABI 7300 Realtime PCR system (Applied Biosystem, Foster City, CA, USA) according to the manufacturer’s instructions. For three genes, TCF7L1, CAPG, and USP39, two primer pairs were designed per gene, whereas one primer pair was designed for two genes, VAMP8 and RNF181 (Table 1).
To amplify the putative fusion gene USP39/TCF7L1, reverse transcriptase PCR (RT-PCR) was performed with a forward primer from USP39 and a reverse primer from TCF7L1, respectively. The forward primer was designed from exon 6 of USP39 because the breakpoint was located between intron 7 (minimum breakpoint) and intron 10 (maximum breakpoint), and an exon 7 fragment is too small to analyze. The reverse primer was designed complementary to exon 5 of TCF7L1, since the breakpoint lies in intron 3 and exon 4 is too short (Figure 4, Table 1).
To better define the clinical phenotype associated with copy number variation of 2p11.2, we compared this case with previously reported interstitial deletions encompassing 2p11.2 and assigned individual phenotypes to individual genes in the duplicated region.
Ethical approval was granted for this study by an interdisciplinary institutional reviewer board of Georgia Regents University.
Written informed consent was obtained from the patient’s mother for the publication of this report and any accompanying images.
Array comparative genomic hybridization
Fluorescent in situ hybridization
Real-time quantitative PCR
Real-time reverse transcriptase quantitative PCR.
This paper is dedicated to Paulita, who lost her battle with multisystem syndrome on September 6th of 2012. She was the beloved daughter and sister of the family. We thank Hyun Min Cho for performing q-PCR and qRT-PCR.
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