GENE-40493; No. of pages: 5; 4C: 2, 3 Gene xxx (2015) xxx–xxx
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A novel 47.2 Mb duplication on chromosomal bands Xq21.1–25 associated with mental retardation Zhijuan Jin a,b,1, Li Yu c,1, Juan Geng d, Jian Wang d, Xingming Jin b, Hong Huang a,⁎ a
MOE — Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, PR China Department of Developmental and Behavioral Pediatrics, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, PR China Institutes of Biomedical Sciences, Fudan University, Shanghai 200433, PR China d Institutes of Pediatric Translational Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, PR China b c
a r t i c l e
i n f o
Article history: Received 2 December 2014 Received in revised form 20 April 2015 Accepted 22 April 2015 Available online xxxx Keywords: Xq21.1–25 Duplication Mental retardation Array CGH
a b s t r a c t We present array comparative genomic hybridization (aCGH) characterization of a novel Xq21.1–25 duplication in a 2-year-old girl with facial dysmorphism, mental retardation and short stature. Analysis of aCGH results revealed a 47,232 kb duplication region that harbored 231 RefSeq genes, including 32 OMIM genes. Ten genes (i.e., ZNF711, SRPX2, RAB40AL, MID2, ACSL4, PAK3, UBE2A, UPF3B, CUL4B, and GRIA3) in the duplication interval have been associated with mental retardation. We discuss the genotype–phenotype correlation in this case. Our case provides evidence for an association of mental retardation with X chromosome duplication. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Genes influencing cognitive function are more often found on the X chromosome than on autosomes. In X-linked mental retardation (XLMR), males are more commonly affected than females. XLMR is estimated to have a frequency of one in 1000 in males (Chiurazzi et al., 2008). Males with duplication of a portion of Xq have features such as short stature, mental retardation, hypotonia, feeding difficulties, and facial abnormalities including epicanthic folds and ptosis. The relationship between phenotype and X chromosome duplications in females remains unclear. Often females with Xq duplications are phenotypically normal, or affected with short stature only. A literature search for females with pure Xq duplications and abnormal phenotypes identified 16 reported cases (Armstrong et al., 2003). Some traits are relatively frequent among these females; i.e., intrauterine growth retardation, short stature, microcephaly, developmental delay/mental retardation, and hypotonia. Approximately 90 genes involved in XLMR have now been identified through genetic linkage analysis and positional cloning, candidate gene Abbreviations: CNV, copy number variation; MR, mental retardation; aCGH, array comparative genomic hybridization; Mb, megabase; NMD, nonsense-mediated mRNA decay; OMIM, Online Mendelian Inheritance in Man; RT-PCR, reverse transcription polymerase chain reaction; XLMR, X-linked mental retardation. ⁎ Corresponding author at: No. 300 Expo Village Road, Pudong, Shanghai, PR China. E-mail address: [email protected] (H. Huang). 1 The authors have equal contribution to this study.
analysis or molecular cytogenetic studies. Each of these accounts for only a small number of families with XLMR and the genes involved in most affected families still await identification. Here, we report a 2-year-old girl with a novel Xq interstitial segmental duplication. She manifested mental retardation, facial dysmorphism, and short stature. 2. Material and methods 2.1. Clinical description The two-year-old female patient was the first child of nonconsanguineous parents. She was born at term with a birth weight of 2250 g and the delivery was normal. The neonatal period was otherwise uneventful. The patient was globally delayed, had hypotonia, was incapable of speaking or walking and had bowel incontinence. On examination, she had a weight of 10.1 kg (b 3rd), a height of 76.5 cm (b 3rd), and a head circumference of 44 cm (b 3rd). Her craniofacial dysmorphisms included slightly drooping eyelids, short palpebral fissures, and low set ears (Fig. 1). She also had a high palate and short toes. A hemangioma about 2 × 2 cm was found at the back of her neck. Physical examination revealed a normal respiratory, cardiovascular, and gastrointestinal system. Cerebral resonance magnetic imaging performed at the age of two years was normal. Severe developmental delay was noted with a mental age of about 10 months old according to the Gesell developmental schedule test. The parents were unrelated, and the family history was unremarkable on both sides.
http://dx.doi.org/10.1016/j.gene.2015.04.083 0378-1119/© 2015 Elsevier B.V. All rights reserved.
Please cite this article as: Jin, Z., et al., A novel 47.2 Mb duplication on chromosomal bands Xq21.1–25 associated with mental retardation, Gene (2015), http://dx.doi.org/10.1016/j.gene.2015.04.083
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Fig. 1. Clinical features of a case with mental retardation.
2.2. Array comparative genomic hybridization (aCGH) Blood samples were obtained after written informed consent from parents of the affected patient. Genomic DNA was extracted from blood samples using a Flexigene kit (Qiagen, France). A Nanodrop ND1000 spectrophotometer (Thermo Fisher Scientific, France) was used for determination of DNA concentrations. An Affymetrix cytoscan LD chip was used for aCGH analysis according to the procedures recommended in the Affymetrix cytoscan LD user's guide. The data were finally represented by using Nexus 6.1 (BioDiscovery, Hawthorne, CA, USA). The detected CNV was validated by Quantitative PCR (qPCR) and conformed retrospectively when looking at array-CGH data.
2.3. Genomic quantitative PCR qPCR was performed on genomic DNA, using an ABI 7500 Real-Time PCR System (Applied Biosystems, Foster City, CA). We designed 8 primer sets within Xq21.1–25 region (Table S1). qPCR was carried out in a total volume of 20 μl containing 10 μl of SYBR® Premix Ex Taq™ (TaKaRa Biotechnology, Dalian, China), 0.2 μM of each primer and 10 ng of genomic DNA. Thermal cycling conditions were 95 °C for 30 s, followed by 40 cycles with 95 °C for 5 s and 60 °C for 34 s. The GAPDH gene was selected as the control amplicon. Validation experiments demonstrated that amplification efficiency of the control and all target amplicons were approximately equal. All samples were run in triplicate.
The dosage of each amplicon relative to GAPDH and normalized to control female DNA was determined using the 2−ΔΔCt method. 3. Results Using DNA extracted from the patient's peripheral blood, aCGH detected a 47.2 Mb duplication on the long arm of the X chromosome (Xq21.1q25; Fig. 2). The genomic position of this duplication according to GRCh37/hg19 was chrX: 80,181,934–127,413,858. The duplicated region harbored 231 RefSeq genes, including 32 OMIM genes; i.e., ZNF711, PCDH19, SRPX2, RAB40AL, PLP1, MID2, ACSL4, PAK3, UBE2A, UPF3B, LAMP2, CUL4B, GRIA3, POU3F4, POF1B, CHM, DIAPH2, TIMM8A, BTK, GLA, PRPS1, COL4A6, COL4A5, CHRDL1, DCX, ALG13, PLS3, SLC6A14, NDUFA1, C1GALT1C1, XIAP, and SH2D1A. qPCR analysis of the patient and female genomic control DNA verify the duplication (Table S2). 4. Discussion Partial duplications of the long arm of chromosome X have been associated with abnormal phenotypes including multiple congenital anomalies and mental and developmental delay. It has been shown that the dup(X) chromosome was inherited from the mother in most cases. In this study, we identified a novel Xq21.1-q25 duplication of 47.2 Mb using aCGH in a 2-year-old girl. Facial dysmorphic features and mental retardation were found in this case. Females with dup(Xq) may manifest the phenotypic abnormalities of short stature, mental retardation, and facial dysmorphism. However,
Please cite this article as: Jin, Z., et al., A novel 47.2 Mb duplication on chromosomal bands Xq21.1–25 associated with mental retardation, Gene (2015), http://dx.doi.org/10.1016/j.gene.2015.04.083
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Fig. 2. Comparative array genomic hybridization of the DNA extracted from the patient's peripheral blood showed an Xq21.1q25 duplication.
there is phenotypic diversity in females with dup(X) because of functional disomy restricted to the duplicated material on the X chromosome (Chen et al., 2014), inter-individual differences in the X-inactivation pattern and expression of recessive mutant genes on the active X chromosome, or gene disruption by chromosome rearrangement (Armstrong et al., 2003). In our case, the duplication region was large, which did not influence the X inactivation pattern, but seemed to be associated with an abnormal phenotype. The dosage effects of the Xq duplication were closely related to the phenotypic abnormalities in girls. The genes located in the duplicated region and their associated functions are shown in Table 1. Ten genes (i.e., ZNF711, SRPX2, RAB40AL, MID2, ACSL4, PAK3, UBE2A, UPF3B, CUL4B, and GRIA3) in the duplication interval have been associated with mental retardation. The ZNF711 (OMIM 314990) gene encodes for a zinc finger protein with unknown function. It harbors an amino-terminal potential domain followed by 12 consecutive Zn–C2H2 domains potentially involved in transcriptional activation and sequence-specific DNA binding, respectively (Kleine-Kohlbrecher et al., 2010). ZNF711 includes 7 exons and is expressed in certain areas of the brain and in neural tissues. In 2009, Tarpey et al. (2009) sequenced the coding exons of the X chromosome in 208 families with X-linked mental retardation. They identified two truncating mutations in the ZNF711 gene in two unrelated families. Sismani et al. (2013) also reported a patient with multiple congenital abnormalities who had a prenatally ascertained, maternally inherited 14.8 Mb duplication of Xq13.2–q21.31 including the ZNF711 gene. The SRPX2 (OMIM 300642) gene codes for a secreted sushi repeatcontaining protein expressed in neurons of the human adult brain, including the rolandic area on chromosome Xq22. Mutations in the
SRPX2 gene have been identified as being responsible for rolandic seizures associated with oral and speech dyspraxia and mental retardation in a 3-generation French family (Roll et al., 2006). By in situ hybridization, Western blotting and immunohistochemical analyses, Salmi et al. (2013) found that Srpx2 mRNA and protein were expressed in the embryonic rat brain during various developmental stages. Sia et al. (2013) showed that SRPX2 reduction impaired development of ultrasonic vocalization in mice and suggested that SRPX2 is a synaptogenic factor that plays a role in the pathogenesis of language disorders. The RAB40AL (OMIM 300405) gene has been associated with Martin–Probst X-linked mental retardation syndrome (XRXSMP; OMIM 300519). XRXSMP includes a variety of phenotypes including congenital sensorineural hearing loss, mental retardation, short stature, congenital umbilical hernia, facial dysmorphism, abnormal teeth, widely spaced nipples, and abnormal dermatoglyphics (Martin et al., 2000). Bedoyan et al. (2012) found that RAB40AL was expressed in human kidneys. Recently, Lee et al. (2014) presented an unrelated 20-year-old male with similar manifestations who also had p.D59G in the RAB40AL gene, while Oldak et al. (2014) screened control DNA samples (n = 810) from a general Polish population and identified p.D59G in 8 of 405 males and 12 of 405 females. High prevalence of the p.D59G variant (2.47%) is typical for a common genetic variation observed in asymptomatic individuals. The different results may be explained by different populations in the studies; however, whether the RAB40AL mutation is a disease-causing mutation and the involvement of RAB40AL in XRXSMP remained as questions. The MID2 (OMIM 300204) gene belongs to a subclass of E3 ubiquitin ligase genes and plays a role in microtubule stabilization (Geetha et al., 2014). The MID2 protein contains a RING finger motif, two B boxes,
Please cite this article as: Jin, Z., et al., A novel 47.2 Mb duplication on chromosomal bands Xq21.1–25 associated with mental retardation, Gene (2015), http://dx.doi.org/10.1016/j.gene.2015.04.083
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Table 1 Genes located within the duplicated region Xq21.1-q25 (nucleotides chrX: 80,181,934–127,413,858) genotype–phenotype correlations and their function. Genes
Gene function
Genotype–phenotype correlations
ZNF711 PCDH19 SRPX2 RAB40AL PLP1 MID2 ACSL4 PAK3 UBE2A UPF3B LAMP2 CUL4B GRIA3 POU3F4 POF1B CHM DIAPH2 TIMM8A BTK GLA PRPS1 COL4A6 COL4A5 CHRDL1 DCX ALG13 PLS3 SLC6A14 NDUFA1 C1GALT1C1 XIAP SH2D1A
Zinc finger protein 711 Protocadherin 19 Sushi repeat-containing protein, X-linked, 2 Ras-associated protein RAB40A-like Proteolipid protein 1 Midline 2 ACYL-CoA synthetase long chain family, member 4 p21 protein-activated kinase 3 Ubiquitin-conjugating enzyme E2A UPF3, yeast, homologue of B Lysosome-associated membrane protein 2 Cullin 4B Glutamate receptor, ionotropic, AMPA3 POU domain, class 3, transcription factor 4 Actin-binding protein CHM gene Diaphanous, Drosophila, homologue of, 2 Translocase of inner mitochondrial membrane 8, yeast, homologue of A Bruton agammaglobulinemia tyrosine kinase Galactonsidase, ALPHA Phosphoribosylpyrophosphate synthetase I Collagen, Tppe IV, ALPHA-6 Collagen, Tppe IV, ALPHA-5 Chordin-like 1 Doublecortin ALG13, S. cerevisiae, homologue of Plastin 3 Solute carrier family 6 (neurotransmitter transporter), member 14 NADH-ubiquinone oxidoreductase 1 ALPHA subcomplex, 1 C1GALT1-specific chaperone 1 Inhibitor of apoptosis, X-linked SH2 domain protein 1A
Mental retardation Epileptic encephalopathy, early infantile, 9 Rolandic epilepsy, mental retardation, and speech dyspraxia Mental retardation, X-linked, syndromic, Martin–Probst type Pelizaeus–Merzbacher disease/spastic paraplegia 2, X-linked Mental retardation, X-linked 101 Mental retardation, X-linked 63 Mental retardation, X-linked 30/47 Mental retardation, X-linked syndromic, Nascimento-type Mental retardation, X-linked, syndromic 14 Danon disease Mental retardation, X-linked, syndromic 15 (Cabezas type) Mental retardation, X-linked 94 Deafness, X-linked 2 Premature ovarian failure 2B Choroideremia Premature ovarian failure Deafness, X-linked 1, progressive/Mohr–Tranebjaerg syndrome Agammaglobulinemia and isolated hormone deficiency Fabry disease Arts syndrome Deafness, X-linked 6 Alport syndrome Megalocornea 1, X-linked Lissencephaly, X-linked/Subcortical laminal heteropia, X-linked Congenital disorder of glycosylation, type Is Bone mineral density QTL18, osteoporosis Obesity, susceptibility to, BMIQ11} Mitochondrial complex I deficiency Tn polyagglutination syndrome, somatic Lymphoproliferative syndrome, X-linked, 2 Lymphoproliferative syndrome, X-linked, 1
coiled coil, COS domain, and C-terminal RFP-like domain. Geetha et al. (2014) identified a hemizygous missense mutation in the MID2 gene in affected members of a large family from northern India with Xlinked mental retardation. All six patients who were evaluated had global developmental delay. Facial dysmorphism was not prominent, but several patients had a long face, prominent ears, and a squint or strabismus. The phenotype described is quite similar to the phenotype of the patient in our report. The ACSL4 (OMIM 300157) gene encodes a form of LACS and is expressed in several tissues, including the brain. Mutations in ACSL4 have been associated with non-syndromic X-linked mental retardation (MRX). The enzymatic activity of ACSL4 appears to be critical for neurodevelopment or maintenance to attain a normal mental status, because the mutations associated with MRX reduce the catalytic activity of ACSL4 (Meloni et al., 2002). Using Drosophila larval brain as an in vivo assay system, Zhang et al. (2009) evaluated ACSL4's function in BMP/ Dpp-related brain development and provided insights into the mechanism by which ACSL4 mutations lead to MRX. The PAK3 (OMIM 300142) gene of the Rho subfamily is a critical regulator of signal transduction pathways. The p21-activated kinases (PAKs) are a family of serine/threonine kinases that are central to signal transduction and cellular regulation. PAK3 is activated upon binding the GTP-bound forms of the Rho GTPases CDC42 and RAC1. PAK3 has been reported to be associated with mental retardation (Gedeon et al., 2003; Rejeb et al., 2008). The phenotype was relatively homogeneous and characterized by microcephaly, marked hypotonia, and oromotor dysfunction with drooling and speech difficulties (Peippo et al., 2007). The UBE2A (OMIM 312180) gene and the CUL4B (OMIM 300304) gene both encode the ubiquitin-conjugating enzyme that is involved in ubiquitination of proteins, thus targeting them for degradation through the proteasome or changing their activity or localization. The ubiquitin proteasome system is a critical regulator of synaptic plasticity and long-term memory formation (Grotto et al., 2014). UBE2A includes six exons and is expressed in the brain and lymphocytes. CUL4B includes
22 exons and is expressed ubiquitously. Mutations in the CUL4B gene seem to be a relatively common cause of XLMR associated with aggressive outbursts, seizures, relative macrocephaly, central obesity, hypogonadism, pes cavus, and tremor (Jarome and Helmstetter, 2013). In contrast, only three point mutations have been identified in UBE2A, which resulted in a syndromic form of X-linked ID (XLID) characterized by moderate to severe ID primarily accompanied by seizures, severely impaired/absent speech, facial dysmorphisms, small penis, and hirsutism (Budny et al., 2010; Nascimento et al., 2006). The UPF3B (OMIM 300298) gene is a member of the nonsensemediated mRNA decay (NMD) complex. NMD is of universal biological significance, which has emerged as an important global RNA, DNA, and translation regulatory pathway. RT-PCR detected variable UPF3B expression in all tissues examined, with the highest expression in the testis and fetal brain. Tarpey et al. (2007) identified a missense mutation of UPF3B in a family with nonsyndromic mental retardation. Xu et al. (2013) reported a large Chinese family in which three living males and one deceased male had nonsyndromic mild mental retardation. The GRIA3 (OMIM 305915) gene is a glutamate receptor, which mediates most of the excitatory neurotransmission in the mammalian brain and also participates in processes of synaptic plasticity and efficacy in learning and memory. Expression of GRIA3 is abundant throughout the brain, while expression is low in the spinal cord. Mutations have been identified in GRIA3, which resulted in X-linked mental retardation characterized by delayed psychomotor development since infancy with severely delayed and poor language acquisition (Bonnet et al., 2009; Bonnet et al., 2012). Some other duplicated regions have been reported which were related with mental retardation. Di Benedetto et al. (2014) described Xq25 duplications identified in two unrelated families whose affected members show intellectual disability, distinctive facial phenotype, brain anomalies, and other clinical features. Honda et al. (2010) detected a novel deletion at Xq24 in a 4-year-old and 10-month-old boy with mental retardation. Chen et al. (2011) reported that a duplication of
Please cite this article as: Jin, Z., et al., A novel 47.2 Mb duplication on chromosomal bands Xq21.1–25 associated with mental retardation, Gene (2015), http://dx.doi.org/10.1016/j.gene.2015.04.083
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Xq22.1-q24 with a disruption of the NXF gene cluster in female patients can be associated with clinical manifestations of mental retardation in addition to short stature and premature ovarian failure. In conclusion, the female patients carrying the Xq duplication exhibit a heterogeneous phenotype, although some traits seem to occur more frequently. The heterogeneous clinical features might be due to the relatively small number of patients studied, carrying duplications of different sizes and gene content, or it could be explained by reduced penetrance or variable expressivity. The current knowledge of the function of the genes duplicated is not sufficient to directly link specific clinical features to specific genes; however, it seems reasonable to assume that ZNF711, SRPX2, RAB40AL, MID2, ACSL4, PAK3, UBE2A, UPF3B, CUL4B, and GRIA3 might play a role in the emergence of the clinical phenotype in our patient. With the advent of aCGH, an interstitial segmental duplication can be easily identified. This study also confirmed the power of aCGH in the clinical investigation of the genetic pathogenesis of mental retardation. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.gene.2015.04.083. Conflict of interest The authors declare that they have no conflict of interest. Acknowledgments We thank the support from the patient and the family. This study is further supported by grant from the Shanghai Municipal Commission of Health and Family Planning (no. GW3-32). References Armstrong, L., McGowan-Jordan, J., Brierley, K., Allanson, J.E., 2003. De novo dup(X)(q22.3q26) in a girl with evidence that functional disomy of X material is the cause of her abnormal phenotype. Am. J. Med. Genet. A 116A (1), 71–76. Bedoyan, J.K., Schaibley, V.M., Peng, W., Bai, Y., Mondal, K., Shetty, A.C., et al., 2012. Disruption of RAB40AL function leads to Martin–Probst syndrome, a rare X-linked multisystem neurodevelopmental human disorder. J. Med. Genet. 49 (5), 332–340. Bonnet, C., Leheup, B., Beri, M., Philippe, C., Gregoire, M.J., Jonveaux, P., 2009. Aberrant GRIA3 transcripts with multi-exon duplications in a family with X-linked mental retardation. Am. J. Med. Genet. A 149A (6), 1280–1289. Bonnet, C., Masurel-Paulet, A., Khan, A.A., Beri-Dexheimer, M., Callier, P., Mugneret, F., et al., 2012. Exploring the potential role of disease-causing mutation in a gene desert: duplication of noncoding elements 5′ of GRIA3 is associated with GRIA3 silencing and X-linked intellectual disability. Hum. Mutat. 33 (2), 355–358. Budny, B., Badura-Stronka, M., Materna-Kiryluk, A., Tzschach, A., Raynaud, M., LatosBielenska, A., et al., 2010. Novel missense mutations in the ubiquitination-related gene UBE2A cause a recognizable X-linked mental retardation syndrome. Clin. Genet. 77 (6), 541–551. Chen, C.P., Su, Y.N., Lin, H.H., Chern, S.R., Tsai, F.J., Wu, P.C., et al., 2011. De novo duplication of Xq22.1 –N q24 with a disruption of the NXF gene cluster in a mentally retarded woman with short stature and premature ovarian failure. Taiwan. J. Obstet. Gynecol. 50 (3), 339–344. Chen, C.P., Lin, S.P., Chern, S.R., Kuo, Y.L., Wu, P.S., Chen, Y.T., et al., 2014. Array CGH characterization of an unbalanced X-autosome translocation associated with Xq27.2-qter deletion, 11q24.3-qter duplication and Xq22.3-q27.1 duplication in a girl with primary amenorrhea and mental retardation. Gene 535 (1), 88–92. Chiurazzi, P., Schwartz, C.E., Gecz, J., Neri, G., 2008. XLMR genes: update 2007. Eur. J. Hum. Genet. 16 (4), 422–434.
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Please cite this article as: Jin, Z., et al., A novel 47.2 Mb duplication on chromosomal bands Xq21.1–25 associated with mental retardation, Gene (2015), http://dx.doi.org/10.1016/j.gene.2015.04.083
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Short communication
A novel 47.2 Mb duplication on chromosomal bands Xq21.1–25 associated with mental retardation Zhijuan Jin a,b,1, Li Yu c,1, Juan Geng d, Jian Wang d, Xingming Jin b, Hong Huang a,⁎ a
MOE — Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, PR China Department of Developmental and Behavioral Pediatrics, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, PR China Institutes of Biomedical Sciences, Fudan University, Shanghai 200433, PR China d Institutes of Pediatric Translational Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, PR China b c
a r t i c l e
i n f o
Article history: Received 2 December 2014 Received in revised form 20 April 2015 Accepted 22 April 2015 Available online xxxx Keywords: Xq21.1–25 Duplication Mental retardation Array CGH
a b s t r a c t We present array comparative genomic hybridization (aCGH) characterization of a novel Xq21.1–25 duplication in a 2-year-old girl with facial dysmorphism, mental retardation and short stature. Analysis of aCGH results revealed a 47,232 kb duplication region that harbored 231 RefSeq genes, including 32 OMIM genes. Ten genes (i.e., ZNF711, SRPX2, RAB40AL, MID2, ACSL4, PAK3, UBE2A, UPF3B, CUL4B, and GRIA3) in the duplication interval have been associated with mental retardation. We discuss the genotype–phenotype correlation in this case. Our case provides evidence for an association of mental retardation with X chromosome duplication. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Genes influencing cognitive function are more often found on the X chromosome than on autosomes. In X-linked mental retardation (XLMR), males are more commonly affected than females. XLMR is estimated to have a frequency of one in 1000 in males (Chiurazzi et al., 2008). Males with duplication of a portion of Xq have features such as short stature, mental retardation, hypotonia, feeding difficulties, and facial abnormalities including epicanthic folds and ptosis. The relationship between phenotype and X chromosome duplications in females remains unclear. Often females with Xq duplications are phenotypically normal, or affected with short stature only. A literature search for females with pure Xq duplications and abnormal phenotypes identified 16 reported cases (Armstrong et al., 2003). Some traits are relatively frequent among these females; i.e., intrauterine growth retardation, short stature, microcephaly, developmental delay/mental retardation, and hypotonia. Approximately 90 genes involved in XLMR have now been identified through genetic linkage analysis and positional cloning, candidate gene Abbreviations: CNV, copy number variation; MR, mental retardation; aCGH, array comparative genomic hybridization; Mb, megabase; NMD, nonsense-mediated mRNA decay; OMIM, Online Mendelian Inheritance in Man; RT-PCR, reverse transcription polymerase chain reaction; XLMR, X-linked mental retardation. ⁎ Corresponding author at: No. 300 Expo Village Road, Pudong, Shanghai, PR China. E-mail address: [email protected] (H. Huang). 1 The authors have equal contribution to this study.
analysis or molecular cytogenetic studies. Each of these accounts for only a small number of families with XLMR and the genes involved in most affected families still await identification. Here, we report a 2-year-old girl with a novel Xq interstitial segmental duplication. She manifested mental retardation, facial dysmorphism, and short stature. 2. Material and methods 2.1. Clinical description The two-year-old female patient was the first child of nonconsanguineous parents. She was born at term with a birth weight of 2250 g and the delivery was normal. The neonatal period was otherwise uneventful. The patient was globally delayed, had hypotonia, was incapable of speaking or walking and had bowel incontinence. On examination, she had a weight of 10.1 kg (b 3rd), a height of 76.5 cm (b 3rd), and a head circumference of 44 cm (b 3rd). Her craniofacial dysmorphisms included slightly drooping eyelids, short palpebral fissures, and low set ears (Fig. 1). She also had a high palate and short toes. A hemangioma about 2 × 2 cm was found at the back of her neck. Physical examination revealed a normal respiratory, cardiovascular, and gastrointestinal system. Cerebral resonance magnetic imaging performed at the age of two years was normal. Severe developmental delay was noted with a mental age of about 10 months old according to the Gesell developmental schedule test. The parents were unrelated, and the family history was unremarkable on both sides.
http://dx.doi.org/10.1016/j.gene.2015.04.083 0378-1119/© 2015 Elsevier B.V. All rights reserved.
Please cite this article as: Jin, Z., et al., A novel 47.2 Mb duplication on chromosomal bands Xq21.1–25 associated with mental retardation, Gene (2015), http://dx.doi.org/10.1016/j.gene.2015.04.083
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Fig. 1. Clinical features of a case with mental retardation.
2.2. Array comparative genomic hybridization (aCGH) Blood samples were obtained after written informed consent from parents of the affected patient. Genomic DNA was extracted from blood samples using a Flexigene kit (Qiagen, France). A Nanodrop ND1000 spectrophotometer (Thermo Fisher Scientific, France) was used for determination of DNA concentrations. An Affymetrix cytoscan LD chip was used for aCGH analysis according to the procedures recommended in the Affymetrix cytoscan LD user's guide. The data were finally represented by using Nexus 6.1 (BioDiscovery, Hawthorne, CA, USA). The detected CNV was validated by Quantitative PCR (qPCR) and conformed retrospectively when looking at array-CGH data.
2.3. Genomic quantitative PCR qPCR was performed on genomic DNA, using an ABI 7500 Real-Time PCR System (Applied Biosystems, Foster City, CA). We designed 8 primer sets within Xq21.1–25 region (Table S1). qPCR was carried out in a total volume of 20 μl containing 10 μl of SYBR® Premix Ex Taq™ (TaKaRa Biotechnology, Dalian, China), 0.2 μM of each primer and 10 ng of genomic DNA. Thermal cycling conditions were 95 °C for 30 s, followed by 40 cycles with 95 °C for 5 s and 60 °C for 34 s. The GAPDH gene was selected as the control amplicon. Validation experiments demonstrated that amplification efficiency of the control and all target amplicons were approximately equal. All samples were run in triplicate.
The dosage of each amplicon relative to GAPDH and normalized to control female DNA was determined using the 2−ΔΔCt method. 3. Results Using DNA extracted from the patient's peripheral blood, aCGH detected a 47.2 Mb duplication on the long arm of the X chromosome (Xq21.1q25; Fig. 2). The genomic position of this duplication according to GRCh37/hg19 was chrX: 80,181,934–127,413,858. The duplicated region harbored 231 RefSeq genes, including 32 OMIM genes; i.e., ZNF711, PCDH19, SRPX2, RAB40AL, PLP1, MID2, ACSL4, PAK3, UBE2A, UPF3B, LAMP2, CUL4B, GRIA3, POU3F4, POF1B, CHM, DIAPH2, TIMM8A, BTK, GLA, PRPS1, COL4A6, COL4A5, CHRDL1, DCX, ALG13, PLS3, SLC6A14, NDUFA1, C1GALT1C1, XIAP, and SH2D1A. qPCR analysis of the patient and female genomic control DNA verify the duplication (Table S2). 4. Discussion Partial duplications of the long arm of chromosome X have been associated with abnormal phenotypes including multiple congenital anomalies and mental and developmental delay. It has been shown that the dup(X) chromosome was inherited from the mother in most cases. In this study, we identified a novel Xq21.1-q25 duplication of 47.2 Mb using aCGH in a 2-year-old girl. Facial dysmorphic features and mental retardation were found in this case. Females with dup(Xq) may manifest the phenotypic abnormalities of short stature, mental retardation, and facial dysmorphism. However,
Please cite this article as: Jin, Z., et al., A novel 47.2 Mb duplication on chromosomal bands Xq21.1–25 associated with mental retardation, Gene (2015), http://dx.doi.org/10.1016/j.gene.2015.04.083
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Fig. 2. Comparative array genomic hybridization of the DNA extracted from the patient's peripheral blood showed an Xq21.1q25 duplication.
there is phenotypic diversity in females with dup(X) because of functional disomy restricted to the duplicated material on the X chromosome (Chen et al., 2014), inter-individual differences in the X-inactivation pattern and expression of recessive mutant genes on the active X chromosome, or gene disruption by chromosome rearrangement (Armstrong et al., 2003). In our case, the duplication region was large, which did not influence the X inactivation pattern, but seemed to be associated with an abnormal phenotype. The dosage effects of the Xq duplication were closely related to the phenotypic abnormalities in girls. The genes located in the duplicated region and their associated functions are shown in Table 1. Ten genes (i.e., ZNF711, SRPX2, RAB40AL, MID2, ACSL4, PAK3, UBE2A, UPF3B, CUL4B, and GRIA3) in the duplication interval have been associated with mental retardation. The ZNF711 (OMIM 314990) gene encodes for a zinc finger protein with unknown function. It harbors an amino-terminal potential domain followed by 12 consecutive Zn–C2H2 domains potentially involved in transcriptional activation and sequence-specific DNA binding, respectively (Kleine-Kohlbrecher et al., 2010). ZNF711 includes 7 exons and is expressed in certain areas of the brain and in neural tissues. In 2009, Tarpey et al. (2009) sequenced the coding exons of the X chromosome in 208 families with X-linked mental retardation. They identified two truncating mutations in the ZNF711 gene in two unrelated families. Sismani et al. (2013) also reported a patient with multiple congenital abnormalities who had a prenatally ascertained, maternally inherited 14.8 Mb duplication of Xq13.2–q21.31 including the ZNF711 gene. The SRPX2 (OMIM 300642) gene codes for a secreted sushi repeatcontaining protein expressed in neurons of the human adult brain, including the rolandic area on chromosome Xq22. Mutations in the
SRPX2 gene have been identified as being responsible for rolandic seizures associated with oral and speech dyspraxia and mental retardation in a 3-generation French family (Roll et al., 2006). By in situ hybridization, Western blotting and immunohistochemical analyses, Salmi et al. (2013) found that Srpx2 mRNA and protein were expressed in the embryonic rat brain during various developmental stages. Sia et al. (2013) showed that SRPX2 reduction impaired development of ultrasonic vocalization in mice and suggested that SRPX2 is a synaptogenic factor that plays a role in the pathogenesis of language disorders. The RAB40AL (OMIM 300405) gene has been associated with Martin–Probst X-linked mental retardation syndrome (XRXSMP; OMIM 300519). XRXSMP includes a variety of phenotypes including congenital sensorineural hearing loss, mental retardation, short stature, congenital umbilical hernia, facial dysmorphism, abnormal teeth, widely spaced nipples, and abnormal dermatoglyphics (Martin et al., 2000). Bedoyan et al. (2012) found that RAB40AL was expressed in human kidneys. Recently, Lee et al. (2014) presented an unrelated 20-year-old male with similar manifestations who also had p.D59G in the RAB40AL gene, while Oldak et al. (2014) screened control DNA samples (n = 810) from a general Polish population and identified p.D59G in 8 of 405 males and 12 of 405 females. High prevalence of the p.D59G variant (2.47%) is typical for a common genetic variation observed in asymptomatic individuals. The different results may be explained by different populations in the studies; however, whether the RAB40AL mutation is a disease-causing mutation and the involvement of RAB40AL in XRXSMP remained as questions. The MID2 (OMIM 300204) gene belongs to a subclass of E3 ubiquitin ligase genes and plays a role in microtubule stabilization (Geetha et al., 2014). The MID2 protein contains a RING finger motif, two B boxes,
Please cite this article as: Jin, Z., et al., A novel 47.2 Mb duplication on chromosomal bands Xq21.1–25 associated with mental retardation, Gene (2015), http://dx.doi.org/10.1016/j.gene.2015.04.083
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Table 1 Genes located within the duplicated region Xq21.1-q25 (nucleotides chrX: 80,181,934–127,413,858) genotype–phenotype correlations and their function. Genes
Gene function
Genotype–phenotype correlations
ZNF711 PCDH19 SRPX2 RAB40AL PLP1 MID2 ACSL4 PAK3 UBE2A UPF3B LAMP2 CUL4B GRIA3 POU3F4 POF1B CHM DIAPH2 TIMM8A BTK GLA PRPS1 COL4A6 COL4A5 CHRDL1 DCX ALG13 PLS3 SLC6A14 NDUFA1 C1GALT1C1 XIAP SH2D1A
Zinc finger protein 711 Protocadherin 19 Sushi repeat-containing protein, X-linked, 2 Ras-associated protein RAB40A-like Proteolipid protein 1 Midline 2 ACYL-CoA synthetase long chain family, member 4 p21 protein-activated kinase 3 Ubiquitin-conjugating enzyme E2A UPF3, yeast, homologue of B Lysosome-associated membrane protein 2 Cullin 4B Glutamate receptor, ionotropic, AMPA3 POU domain, class 3, transcription factor 4 Actin-binding protein CHM gene Diaphanous, Drosophila, homologue of, 2 Translocase of inner mitochondrial membrane 8, yeast, homologue of A Bruton agammaglobulinemia tyrosine kinase Galactonsidase, ALPHA Phosphoribosylpyrophosphate synthetase I Collagen, Tppe IV, ALPHA-6 Collagen, Tppe IV, ALPHA-5 Chordin-like 1 Doublecortin ALG13, S. cerevisiae, homologue of Plastin 3 Solute carrier family 6 (neurotransmitter transporter), member 14 NADH-ubiquinone oxidoreductase 1 ALPHA subcomplex, 1 C1GALT1-specific chaperone 1 Inhibitor of apoptosis, X-linked SH2 domain protein 1A
Mental retardation Epileptic encephalopathy, early infantile, 9 Rolandic epilepsy, mental retardation, and speech dyspraxia Mental retardation, X-linked, syndromic, Martin–Probst type Pelizaeus–Merzbacher disease/spastic paraplegia 2, X-linked Mental retardation, X-linked 101 Mental retardation, X-linked 63 Mental retardation, X-linked 30/47 Mental retardation, X-linked syndromic, Nascimento-type Mental retardation, X-linked, syndromic 14 Danon disease Mental retardation, X-linked, syndromic 15 (Cabezas type) Mental retardation, X-linked 94 Deafness, X-linked 2 Premature ovarian failure 2B Choroideremia Premature ovarian failure Deafness, X-linked 1, progressive/Mohr–Tranebjaerg syndrome Agammaglobulinemia and isolated hormone deficiency Fabry disease Arts syndrome Deafness, X-linked 6 Alport syndrome Megalocornea 1, X-linked Lissencephaly, X-linked/Subcortical laminal heteropia, X-linked Congenital disorder of glycosylation, type Is Bone mineral density QTL18, osteoporosis Obesity, susceptibility to, BMIQ11} Mitochondrial complex I deficiency Tn polyagglutination syndrome, somatic Lymphoproliferative syndrome, X-linked, 2 Lymphoproliferative syndrome, X-linked, 1
coiled coil, COS domain, and C-terminal RFP-like domain. Geetha et al. (2014) identified a hemizygous missense mutation in the MID2 gene in affected members of a large family from northern India with Xlinked mental retardation. All six patients who were evaluated had global developmental delay. Facial dysmorphism was not prominent, but several patients had a long face, prominent ears, and a squint or strabismus. The phenotype described is quite similar to the phenotype of the patient in our report. The ACSL4 (OMIM 300157) gene encodes a form of LACS and is expressed in several tissues, including the brain. Mutations in ACSL4 have been associated with non-syndromic X-linked mental retardation (MRX). The enzymatic activity of ACSL4 appears to be critical for neurodevelopment or maintenance to attain a normal mental status, because the mutations associated with MRX reduce the catalytic activity of ACSL4 (Meloni et al., 2002). Using Drosophila larval brain as an in vivo assay system, Zhang et al. (2009) evaluated ACSL4's function in BMP/ Dpp-related brain development and provided insights into the mechanism by which ACSL4 mutations lead to MRX. The PAK3 (OMIM 300142) gene of the Rho subfamily is a critical regulator of signal transduction pathways. The p21-activated kinases (PAKs) are a family of serine/threonine kinases that are central to signal transduction and cellular regulation. PAK3 is activated upon binding the GTP-bound forms of the Rho GTPases CDC42 and RAC1. PAK3 has been reported to be associated with mental retardation (Gedeon et al., 2003; Rejeb et al., 2008). The phenotype was relatively homogeneous and characterized by microcephaly, marked hypotonia, and oromotor dysfunction with drooling and speech difficulties (Peippo et al., 2007). The UBE2A (OMIM 312180) gene and the CUL4B (OMIM 300304) gene both encode the ubiquitin-conjugating enzyme that is involved in ubiquitination of proteins, thus targeting them for degradation through the proteasome or changing their activity or localization. The ubiquitin proteasome system is a critical regulator of synaptic plasticity and long-term memory formation (Grotto et al., 2014). UBE2A includes six exons and is expressed in the brain and lymphocytes. CUL4B includes
22 exons and is expressed ubiquitously. Mutations in the CUL4B gene seem to be a relatively common cause of XLMR associated with aggressive outbursts, seizures, relative macrocephaly, central obesity, hypogonadism, pes cavus, and tremor (Jarome and Helmstetter, 2013). In contrast, only three point mutations have been identified in UBE2A, which resulted in a syndromic form of X-linked ID (XLID) characterized by moderate to severe ID primarily accompanied by seizures, severely impaired/absent speech, facial dysmorphisms, small penis, and hirsutism (Budny et al., 2010; Nascimento et al., 2006). The UPF3B (OMIM 300298) gene is a member of the nonsensemediated mRNA decay (NMD) complex. NMD is of universal biological significance, which has emerged as an important global RNA, DNA, and translation regulatory pathway. RT-PCR detected variable UPF3B expression in all tissues examined, with the highest expression in the testis and fetal brain. Tarpey et al. (2007) identified a missense mutation of UPF3B in a family with nonsyndromic mental retardation. Xu et al. (2013) reported a large Chinese family in which three living males and one deceased male had nonsyndromic mild mental retardation. The GRIA3 (OMIM 305915) gene is a glutamate receptor, which mediates most of the excitatory neurotransmission in the mammalian brain and also participates in processes of synaptic plasticity and efficacy in learning and memory. Expression of GRIA3 is abundant throughout the brain, while expression is low in the spinal cord. Mutations have been identified in GRIA3, which resulted in X-linked mental retardation characterized by delayed psychomotor development since infancy with severely delayed and poor language acquisition (Bonnet et al., 2009; Bonnet et al., 2012). Some other duplicated regions have been reported which were related with mental retardation. Di Benedetto et al. (2014) described Xq25 duplications identified in two unrelated families whose affected members show intellectual disability, distinctive facial phenotype, brain anomalies, and other clinical features. Honda et al. (2010) detected a novel deletion at Xq24 in a 4-year-old and 10-month-old boy with mental retardation. Chen et al. (2011) reported that a duplication of
Please cite this article as: Jin, Z., et al., A novel 47.2 Mb duplication on chromosomal bands Xq21.1–25 associated with mental retardation, Gene (2015), http://dx.doi.org/10.1016/j.gene.2015.04.083
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Xq22.1-q24 with a disruption of the NXF gene cluster in female patients can be associated with clinical manifestations of mental retardation in addition to short stature and premature ovarian failure. In conclusion, the female patients carrying the Xq duplication exhibit a heterogeneous phenotype, although some traits seem to occur more frequently. The heterogeneous clinical features might be due to the relatively small number of patients studied, carrying duplications of different sizes and gene content, or it could be explained by reduced penetrance or variable expressivity. The current knowledge of the function of the genes duplicated is not sufficient to directly link specific clinical features to specific genes; however, it seems reasonable to assume that ZNF711, SRPX2, RAB40AL, MID2, ACSL4, PAK3, UBE2A, UPF3B, CUL4B, and GRIA3 might play a role in the emergence of the clinical phenotype in our patient. With the advent of aCGH, an interstitial segmental duplication can be easily identified. This study also confirmed the power of aCGH in the clinical investigation of the genetic pathogenesis of mental retardation. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.gene.2015.04.083. Conflict of interest The authors declare that they have no conflict of interest. Acknowledgments We thank the support from the patient and the family. This study is further supported by grant from the Shanghai Municipal Commission of Health and Family Planning (no. GW3-32). References Armstrong, L., McGowan-Jordan, J., Brierley, K., Allanson, J.E., 2003. De novo dup(X)(q22.3q26) in a girl with evidence that functional disomy of X material is the cause of her abnormal phenotype. Am. J. Med. Genet. A 116A (1), 71–76. Bedoyan, J.K., Schaibley, V.M., Peng, W., Bai, Y., Mondal, K., Shetty, A.C., et al., 2012. Disruption of RAB40AL function leads to Martin–Probst syndrome, a rare X-linked multisystem neurodevelopmental human disorder. J. Med. Genet. 49 (5), 332–340. Bonnet, C., Leheup, B., Beri, M., Philippe, C., Gregoire, M.J., Jonveaux, P., 2009. Aberrant GRIA3 transcripts with multi-exon duplications in a family with X-linked mental retardation. Am. J. Med. Genet. A 149A (6), 1280–1289. Bonnet, C., Masurel-Paulet, A., Khan, A.A., Beri-Dexheimer, M., Callier, P., Mugneret, F., et al., 2012. Exploring the potential role of disease-causing mutation in a gene desert: duplication of noncoding elements 5′ of GRIA3 is associated with GRIA3 silencing and X-linked intellectual disability. Hum. Mutat. 33 (2), 355–358. Budny, B., Badura-Stronka, M., Materna-Kiryluk, A., Tzschach, A., Raynaud, M., LatosBielenska, A., et al., 2010. Novel missense mutations in the ubiquitination-related gene UBE2A cause a recognizable X-linked mental retardation syndrome. Clin. Genet. 77 (6), 541–551. Chen, C.P., Su, Y.N., Lin, H.H., Chern, S.R., Tsai, F.J., Wu, P.C., et al., 2011. De novo duplication of Xq22.1 –N q24 with a disruption of the NXF gene cluster in a mentally retarded woman with short stature and premature ovarian failure. Taiwan. J. Obstet. Gynecol. 50 (3), 339–344. Chen, C.P., Lin, S.P., Chern, S.R., Kuo, Y.L., Wu, P.S., Chen, Y.T., et al., 2014. Array CGH characterization of an unbalanced X-autosome translocation associated with Xq27.2-qter deletion, 11q24.3-qter duplication and Xq22.3-q27.1 duplication in a girl with primary amenorrhea and mental retardation. Gene 535 (1), 88–92. Chiurazzi, P., Schwartz, C.E., Gecz, J., Neri, G., 2008. XLMR genes: update 2007. Eur. J. Hum. Genet. 16 (4), 422–434.
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Please cite this article as: Jin, Z., et al., A novel 47.2 Mb duplication on chromosomal bands Xq21.1–25 associated with mental retardation, Gene (2015), http://dx.doi.org/10.1016/j.gene.2015.04.083
