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Clinical and molecular delineation of duplication 9p24.3q21.11 in a patient with psychotic behavior
Gene 560 (2015) 124–127
Contents lists available at ScienceDirect
Gene journal homepage: www.elsevier.com/locate/gene
Short communication
Clinical and molecular delineation of duplication 9p24.3q21.11 in a patient with psychotic behavior Lizeth Martínez-Jacobo a, Rocío Ortíz-López a,b, Alfredo Rizo-Méndez c, Viridiana García-Molina c, Sandra K. Santuario-Facio b, Fernando Rivas d, Augusto Rojas-Martínez a,b,⁎ a
Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo León, Monterrey, Mexico Unidad de Genómica, Centro de Investigación y Desarrollo en Ciencias de la Salud, Universidad Autónoma de Nuevo León, Monterrey, Mexico Servicio de Psiquiatría, Hospital Civil de Guadalajara, Guadalajara, Mexico d Hospital General de Occidente, Secretaría de Salud Jalisco, Guadalajara, Mexico b c
a r t i c l e
i n f o
Article history: Received 1 November 2014 Received in revised form 1 February 2015 Accepted 6 February 2015 Available online 7 February 2015 Keywords: 9p duplication syndrome Psychosis Autism
a b s t r a c t This article describes a 19-year-old female with mild facial dysmorphism, asociality, decreased school performance, and psychotic behavior in whom the karyotype showed an extra-chromosomal marker characterized as 9p24.3–9q21.11 duplication by array-CGH. The 69 Mbp duplicated segment in this patient includes the critical 9p duplication syndrome region, the GLDC and C90RF72 genes associated with psychotic behavior and other conduct disorders, and a potential locus for autism. © 2015 Elsevier B.V. All rights reserved.
1. Introduction
2. Case presentation
The 9p trisomy represents the 4th most common life-compatible autosomal trisomy and one of the most clinically characterized chromosomal abnormalities after trisomies 21, 13, and 18 (Temtamy et al., 2007; San Román Muñoz et al., 2004). Its severity correlates with the extension of the involved chromosomal segment (Temtamy et al., 2007). Craniofacial abnormalities and intellectual disability (ID) are common, but to date only one case of 9p duplication featuring autism (Abu-Amero et al., 2010) has been described in trisomy 9p. Most of the 9p duplication cases originate as meiotic unbalances in parents with balanced translocations (Haddad et al., 1996). This article describes a young female patient affected by ID, psychotic episodes, and craniofacial dysmorphism.
A 19 year-old-female patient from a rural area was attended at the Psychiatric Service of the Hospital Civil de Guadalajara (Mexico) due to an acute psychotic episode started on the day before the visit. The episode consisted of disorganized speech, auditory and visual hallucinations, mystic and persecutory delusions and disorientation. Once the medical causes were discarded, including neuroinfection and encephalitis by magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) analysis, the patient received treatment with olanzapine and valproate showing a significant improvement after the first week of therapy. There were previous psychotic episodes with full interepisode remission. The patient is referred to have poor socialization, but there are no additional symptoms. The patient is a single child from a nonconsanguineous and reportedly healthy couple. After a surveilled pregnancy, the patient was delivered by cesarean section due to acute fetal distress, and birth weight and size are not known. In addition to persistent enuresis until 7 years old, the remaining psychomotor development is unnoticeable. She started scholarity at age 4 y.o. and showed poor learning and social disabilities. Menarche happened at 10 y.o. and sexual development was normal. Physical examination showed a well oriented girl with a cooperative attitude during the interview, but psychomotor hyperreactivity and alterations in logical reasonings were noted. Patient was 1.55 cm tall and her weight was 49.5 kg, with a BMI of 20.6. The exam showed micrognathia, arched palate, bulbous nose, downturned corners of mouth, low set ears, short neck and brachymesodactyly. An umbilical hernia was also observed. The rest of
Abbreviations: Array-CGH, array based comparative genomic hybridization; BMI, body mass index; C9orf123 gene, chromosome 9 open reading frame 72; C9orf66 gene, chromosome 9 open reading frame 66; C9orf72 gene, chromosome 9 open reading frame 72; CNVs, copy number variations; DECIPHER, DatabasE of Genomic variants and Phenotype in Humans Using Ensembl Resources; DOCK8 gene, dedicator of cytokinesis 8; FOXD4 gene, forkhead box D4; GLDC gene, glycine dehydrogenase; ID, intellectual disability; KANK1 (ANKRD15) gene, KN motif and ankyrin repeat domains 1; MRI, magnetic resonance imaging; NMDA, N-methyl-D-aspartate; PTPRD gene, protein tyrosine phosphatase receptor type D; UCSC Genome Browser, University of California Santa Cruz Genome Browser. ⁎ Corresponding author at: Facultad de Medicina and Centro de Investigación y Desarrollo en Ciencias de la Salud, Universidad Autónoma de Nuevo León, Carlos Canseco S.N., Colonia Mitras Centro, Monterrey C.P. 64460, Mexico. E-mail addresses: [email protected], [email protected] (A. Rojas-Martínez).
http://dx.doi.org/10.1016/j.gene.2015.02.010 0378-1119/© 2015 Elsevier B.V. All rights reserved.
L. Martínez-Jacobo et al. / Gene 560 (2015) 124–127
the clinical examination, electroencephalogram, cardiologic evaluation, and standard cranial radiographs and MRI studies were normal. 3. Material and methods 3.1. Chromosomal analysis Before the studies, the patient's mother was informed about the genetic studies, including aCGH, and signed the consent. Initial cytogenetic analyses were performed by standard 72 h lymphocyte culture (PB-MAX, Gibco®) and G-banding on 30 metaphases, at a resolution of 450 bands approximately. An additional EDTA-anticoagulated blood sample was used for DNA isolation and aCGH studies. Parental samples for chromosome studies were not available. 3.2. Array CGH Genomic DNA (250 ng) was obtained from 3 ml of peripheral blood by Qiagen DNeasy Blood & Tissue Kit (Qiagen, Hilden, Germany), digested with restriction enzymes Sty I and Nsp I (New England BioLabs, Ipswich, MA), and ligated to Sty I or Nsp I adaptors, respectively. After PCR amplification, random fragmentation, purification and labeling procedures, samples were hybridized to Affymetrix GenomeWide SNP 6.0 arrays (Affymetrix, Santa Clara, CA) for 16–18 h in a hybridization oven. Washing and staining of the arrays were performed using the fluidics station 450 (Affymetrix); array images were acquired using the Affymetrix GeneChip Scanner 3000; Affymetrix, and analyzed by using the Genotyping Console v4.0 software. 4. Results The patient's 47,XX,+mar karyotype found in all cells was reinterpreted after molecular studies including a supernumerary marker 9pter–q21.11. The aCGH study demonstrated that the marker corresponded to a 69 Mb duplicated segment of chromosome 9 (genomic positions 46, 587-69, 186, 399), involving 31,069 markers and 280 genes (including miRNAs and hypothetic protein-genes) (NCBI36/ hg18), indicative of a partial trisomy 9pter–q21.11 (Fig. 1). The final karyotype for this patient is 47,XX,+mar.arr9p24.3q21.11 (46, 587-69, 186, 399) × 3 (Fig. 1). This duplication involves: a) the critical region for the 9p duplication syndrome, b) the GLDC gene associated with non-ketotic hyperglycinemia (NKH) (Kure et al., 1997), c) the C90RF72 gene
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associated with psychotic behavior (Galimberti et al., 2013), d) a locus associated with autism (Abu-Amero et al., 2010), and e) several genes associated with ID and to additional disturbances of conduct, like KANK1, DOCK8, FOXD4, C9orf123, and PTPRD. Similar duplications have been also reported (Lin et al., 1977; Stoll et al., 1992; Temtamy et al., 2007; Bonaglia et al., 2002; Di Bartolo et al., 2012) (Fig.2). No additional genomic disturbances were observed.
5. Discussion A patient with mild features of 9p duplication syndrome and psychotic episodes had an extra marker 9pter → q21.11 showing partial trisomy of chromosome 9. In spite of the marker chromosome's size, its identification using only G bands was not possible. Similar cases of partial trisomies of chromosome 9 in which marker chromosomes were identified by complementary techniques have been reported by Lin et al. (1977) and Temtamy et al. (2007). The proposita's karyotype showed a likely stable extra 9p marker. The marker's mitotic stability indicates that the broken end is capped with a functional telomere be it a neotelomere or captured from 9q or another chromosome. Although we did not analyze the chromosomes of the patient's parents and therefore cannot exclude a parental translocation (e.g., Teraoka et al., 2001; family 2 in Vázquez-Cárdenas et al., 2007), the family history rather supports a de novo origin as it has been documented for other extra 9p chromosomes (patient 4 in Temtamy et al., 2007; Abu-Amero et al., 2010). The region shares a duplicated segment with the 9p duplication syndrome critical region (9p22.3–9p22.2) (Abu-Amero et al., 2010), which partially explains her dysmorphic features. The clinical picture of the 9p duplication syndrome mainly includes ID, craniofacial malformations as microcephaly, micrognathia, downturned corners of the mouth among others, and distal phalangeal hypoplasia (Sirisena et al., 2013). There is only one report of autism (Abu-Amero et al., 2010) but no cases of psychotic disturbances in patients with 9p duplication. The search of related cases in DECIPHER (Firth et al., 2009) database displays 186 cases related to the duplicated segment in this patient. In addition to the physical malformations described in them, there are 20 instances of autism, 5 of psychosis, and 10 related to other psychiatric conditions, such as aggressive behavior. Among the genes involved in this duplicated region, GLDC, C9orf66, DOCK8, FOXD4, C9orf72, and KANK1 have been associated with altered neurodevelopment.
Fig. 1. (A) Patient's karyotype showing a marker chromosome. (B) Microarray image of duplicate region of chromosome 9 from Genotyping Console v.4 Software.
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L. Martínez-Jacobo et al. / Gene 560 (2015) 124–127
Fig. 2. Reported cases with 9p imbalances overlapping the duplicated region in the present case. Vertical green lines indicate potential loci for autism. Vertical black lines indicate the critical region for the 9p duplication syndrome. ID.255468, ID.248471, ID.257283, ID.277528, ID.271336, ID.279709 and ID.287059 are cases found in the DECIPHER database.
Psychosis, as reported in this patient, was also observed in three previously reported patients with 9p imbalances involving the GLDC and KDM4C genes (Firth et al., 2009) (Fig. 3). The GLDC gene codifies glycine decarboxylase. Glycine is a well-established co-agonist
Fig. 3. Common genes identified in reported cases of 9p imbalances and psychosis/ psychiatric behavior in DECIPHER database. Red = deletions and blue = duplications. (A) Cases with psychosis. (B) Cases with psychiatric behavior.
neurotransmitter with glutamate at N-methyl-D-aspartate (NMDA) receptors (Gray and Nicoll, 2012; Nonog et al., 2003). Mutations in GLDC gene produce non-ketotic hyperglycinemia and severe neural injury (Kure et al., 1997). GLDC and KDM4C gene duplications were already reported as a CNV of uncertain significance for schizophrenia and epilepsy (Stewart et al., 2011). Kantrowitz and Javitt (2010) hypothesized that GLDC gene duplications increased glycine catabolism and NMDA receptor hypoactivity, which may be related to schizophrenic phenotype, and there are some pilot studies evaluating the administration of glycine for the treatment of psychotic patients (Kantrowitz and Javitt, 2010; Woods et al., 2013). Duplication of GLDC was also reported in a patient with seizures (Olson et al., 2014) and in three instances of familial glioblastoma (Andersson et al., 2014). C9orf66, DOCK8 and KANK1 CNVs were also found in 6/10 patients with psychiatric behavior reported in DECIPHER and this report contributes with an additional case (Fig. 3). DOCK8 and KANK1 have been associated with ID (Griggs et al., 2008; Lerer et al., 2005; Recalcati et al., 2012). C9orf66 function remains unknown (Griggs et al., 2008). Abu-Amero et al. (2010) reported a mosaic 9p duplication patient and suggested a candidate locus for autism in 9p24.3. After this report, other researchers identified a CNV probably associated with autism in the same region that involves the C9orf66, CBWD1, DOCK8 and FOXD4 genes (Pinto et al., 2010; Sanders et al., 2011). This CNV is also duplicated in the reported patient, in whom the diagnosis of autism is debatable, although her associability is remarkable. The genetics of psychiatric disorders is complex (Harris, 2010). However, with the use of modern genomic tools has been identified CNVs that confer risk to disorders like autism and schizophrenia (Stefansson et al., 2014). This genetic complexity dictates that assessment of the biomedical relevance of copy-number variants and the genes that they affect needs to be considered in an integrated context (Cook and Scherer, 2008). FOXD4, C9orf123, C9orf72 and PTPRD genes, duplicated in this patient, have been involved in behavioral disorders. For instance, FOXD4
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mutations have been associated with obsessive–compulsive disorder and suicidal behavior, as well as autism; C9orf123 ones with attention deficit and disruptive behavior disorders, and those of PTPRD with attention deficit/hyperactivity disorder. The C9orf72 gene codifies for an uncharacterized protein present in the brain tissue and a dynamic mutation of this gene consisting of hexanucleotide repeats is associated with frontotemporal dementia and psychosis (Snowden et al., 2012; Kent et al., 2002). To summarize, since duplicated genomic region in the present case contains genes related to abnormal neurodevelopment and behavior, molecular abnormalities may explain the malformed phenotype and the mental and behavioral disorders. Observations in the reported patient sustain that GLDC and C9orf72 genes could be implicated in schizophrenia and psychosis; support the involvement of 9p24.3 as a locus associated with autism (UCSC-Genome Browser); suggest that genes KANK1, DOCK8, and FOXD4 are related to autistic trait; and also support the involvement of C9orf123, PTPRD and FOXD4 in ID and behavioral disorders. 6. Conclusion This article reports a 9p duplication patient with malformations, associability and psychotic behavior. Expression of duplicated genes may explain the malformed phenotype and the mental and behavioral disorders, including psychotic traits. Acknowledgments We would like to thank the patient's mother for their cooperation along this study. Lizeth Martínez-Jacobo is supported by a CONACYT (Mexico) scholarship. References Abu-Amero, K.K., Hellani, A.M., Salih, M., Seidahmed, M.Z., Elmalik, T.S., Zidan, G., Bosley, T.M., 2010. A de novo marker chromosome derived from 9p in a patient with 9p partial duplication syndrome and autism features: genotype–phenotype correlation. BMC Med. Genet. 11, 135. http://dx.doi.org/10.1186/1471-2350-11-135. Andersson, U., Wibom, C., Cederquist, K., Aradottir, S., Borg, A., et al., 2014. Germline rearrangements in families with strong family history of glioma and malignant melanoma, colon, and breast cancer. Neuro-Oncology 1–8 http://dx.doi.org/10.1093/neuonc/ nou052. Bonaglia, M.C., Giorda, R., Carrozzo, R., Roncoroni, M.E., Grasso, R., Borgatti, R., Zuffardi, O., 2002. 20-Mb duplication of chromosome 9p in a girl with minimal physical findings and normal IQ: narrowing of the 9p duplication critical region to 6 Mb. Am. J. Med. Genet. 112 (2), 154–159. Cook, E., Scherer, S., 2008. Copy-number variations associated with neuropsychiatric conditions. Nature 455, 919–923. http://dx.doi.org/10.1038/nature07458. Di Bartolo, D.L., El Naggar, M., Owen, R., Sahoo, T., Gilbert, F., Pulijaal, V.R., Mathew, S., 2012. Characterization of a complex rearrangement involving duplication and deletion of 9p in an infant with craniofacial dysmorphism and cardiac anomalies. Mol. Cytogenet. 5, 31. http://dx.doi.org/10.1186/1755-8166-5-31. Firth, H.V., et al., 2009. DECIPHER: database of chromosomal imbalance and phenotype in humans using ensembl resources. Am. J. Hum. Genet. 84, 524–533. http://dx.doi.org/ 10.1016/j.ajhg.2009.03.010. Galimberti, D., Fenoglio, C., Serpente, M., Villa, C., Bonsi, R., et al., 2013. Autosomal dominant frontotemporal lobar degeneration due to the C9ORF72 hexanucleotide repeat expansion: late-onset psychotic clinical presentation. Biol. Psychiatry 74 (5), 384–391. http://dx.doi.org/10.1016/j.biopsych.2013.01.031. Gray, J.A., Nicoll, R.A., 2012. Thinking outside the synapse: glycine at extrasynaptic NMDA receptors. Cell 150 (3), 455–456. http://dx.doi.org/10.1016/j.cell.2012.07.013. Griggs, B.L., Ladd, S., Saul, R.A., DuPont, B.R., Srivastava, A.K., 2008. Dedicator of cytokinesis 8 is disrupted in two patients with mental retardation and developmental disabilities. Genomics 91 (2), 195–202.
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Haddad, B.R., Lin, A.E., Wyandt, H., Milunsky, A., 1996. Molecular cytogenetic characterisation of the first familial case of partial 9p duplication (p22p24). J. Med. Genet. 33 (12), 1045–1047. Harris, J.C., 2010. Advances in understanding behavioral phenotypes in neurogenetic syndromes. Am. J. Med. Genet. 154C, 389–399. http://dx.doi.org/10.1002/ajmg.c.30276. Kantrowitz, J.T., Javitt, D.C., 2010. N-methyl-D-aspartate (NMDA) receptor dysfunction or dysregulation: the final common pathway on the road to schizophrenia? Brain Res. 83, 108–121. Kent, W.J., Sugnet, C.W., Furey, T.S., Roskin, K.M., Pringle, T.H., Zahler, A.M., Haussler, D., 2002. UCSC Genome Browser: the human genome browser at UCSC. Genome Res. 12 (6), 996–1006. Kure, S., Tada, K., Narisawa, K., 1997. Nonketotic hyperglycinemia: biochemical, molecular, and neurological aspects. Jpn. J. Hum. Genet. 42 (1), 13–22. Lerer, I., Sagi, M., Meiner, V., Cohen, T., Zlotogora, J., Abeliovich, D., 2005. Deletion of the ANKRD15 gene at 9p24.3 causes parent-of-origin-dependent inheritance of familial cerebral palsy. Hum. Mol. Genet. 14, 3911–3920. Lin, C.C., Holman, G., Sewell, L., Bowen, P., Biederman, B., 1977. Interchromosomal duplication for the short arm of chromosome no. 9: report of three cases due to a familial translocation t(9; 11) and one case with a de novo 47, XX, +9p karyotype. J. Ment. Defic. Res. 21, 309–329. Nonog, Y., Huang, Y.Q., Ju, W., Kalia, L.V., Ahmadian, G., Wang, Y.T., Salter, M.W., 2003. Glycine binding primes NMDA receptor internalization. Nature 422, 302–307. Olson, H., Shen, Y., Avallone, J., Sheidley, B.R., Pinsky, R., Bergin, A.M., et al., 2014. Copy number variation plays an important role in clinical epilepsy. Ann. Neurol. 75 (6), 943–958. http://dx.doi.org/10.1002/ana.24178. Pinto, D., Pagnamenta, A., Klei, L., Anney, R., 2010. Functional impact of global rare copy number variation in autism spectrum disorders. Nature 466 (7304), 368–372. http://dx.doi.org/10.1038/nature09146.Functional. Recalcati, M.P., Bellini, M., Norsa, L., Ballarati, L., Caselli, R., Russo, S., Larizza, L., Giardino, D., 2012. Complex rearrangement involving 9p deletion and duplication in a syndromic patient: genotype/phenotype correlation and review of the literature. Gene 502, 40–45. San Román Muñoz, M., Herranz Fernández, J.L., Tejerina Puente, A., Arteaga ManjónCabeza, R., López Grondona, F., 2004. Trisomy 9p: report of two new cases. Ann. Pediatr. 61 (4), 336–339. Sanders, S.J., Ercan-Sencicek, A.G., Hus, V., Luo, R., Murtha, M.T., et al., 2011. Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron 70 (5), 863–885. http://dx.doi.org/ 10.1016/j.neuron.2011.05.002. Sirisena, N.D., Wijetunge, U.K., de Silva, R., Dissanayake, V.H., 2013. Child with deletion 9p syndrome presenting with craniofacial dysmorphism, developmental delay, and multiple congenital malformations. Case Rep. Genet. http://dx.doi.org/10.1155/2013/ 785830. Snowden, J.S., Rollinson, S., Thompson, J.C., Harris, J.M., Stopford, C.L., et al., 2012. Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations. Brain 135 (3), 693–708. http://dx.doi.org/10.1093/brain/ awr355. Stefansson, H., Meyer-Lindenberg, A., Steinberg, Stacy, Magnusdottir, B., Morgen, K., et al., 2014. CNVs conferring risk of autism or schizophrenia affect cognition in controls. Nature 505, 361–366. http://dx.doi.org/10.1038/nature12818. Stewart, L.R., Hall, A.L., Kang, S.H., Shaw, C.A., Beaudet, A.L., 2011. High frequency of known copy number abnormalities and maternal duplication 15q11–q13 in patients with combined schizophrenia and epilepsy. BMC Med. Genet. 12, 154. http://dx.doi. org/10.1186/1471-2350-12-154. Stoll, C., Chognot, D., Halb, A., Luckel, J.C., 1992. Trisomy 9 mosaicism in two girls with multiple congenital malformations and mental retardation. J Med Genet 30, 433–435. Temtamy, S.A., Kamel, A.K., Ismail, S., Helmy, N.A., Aglan, M.S., El Gammal, M., El Ruby, M., Mohamed, A.M., 2007. Phenotypic and cytogenetic spectrum of 9p trisomy. Genet. Couns. 18 (1), 29–48. Teraoka, M., Narahara, K., Yokoyama, Y., Ninomiya, S., Mizuta, S., Une, T., Seino, Y., 2001. Maternal origin of a unique extra chromosome, der(9)(pter → q13::q13 → q12:) in a girl with typical trisomy 9p syndrome. Am. J. Med. Genet. 102 (1), 25–28. Vázquez-Cárdenas, A., Vásquez-Velásquez, A.I., Barros-Núñez, P., Mantilla-Capacho, J., Rocchi, M., Rivera, H., 2007. Familial whole-arm translocations (1;19), (9;13), and (12;21): a review of 101 constitutional exchanges. J. Appl. Genet. 48 (3), 261–268. Woods, S.W., Walsh, B.C., Hawkins, K.A., Miller, T.J., Saksa, J.R., D'Souza, D.C., Pearlson, G.D., Javitt, D.C., McGlashan, T.H., Krystal, J.H., 2013. Glycine treatment of the risk syndrome for psychosis: report of two pilot studies. Eur. Neuropsychopharmacol. 23 (8), 931–940. http://dx.doi.org/10.1016/j.euroneuro.2012.09.008.
Contents lists available at ScienceDirect
Gene journal homepage: www.elsevier.com/locate/gene
Short communication
Clinical and molecular delineation of duplication 9p24.3q21.11 in a patient with psychotic behavior Lizeth Martínez-Jacobo a, Rocío Ortíz-López a,b, Alfredo Rizo-Méndez c, Viridiana García-Molina c, Sandra K. Santuario-Facio b, Fernando Rivas d, Augusto Rojas-Martínez a,b,⁎ a
Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo León, Monterrey, Mexico Unidad de Genómica, Centro de Investigación y Desarrollo en Ciencias de la Salud, Universidad Autónoma de Nuevo León, Monterrey, Mexico Servicio de Psiquiatría, Hospital Civil de Guadalajara, Guadalajara, Mexico d Hospital General de Occidente, Secretaría de Salud Jalisco, Guadalajara, Mexico b c
a r t i c l e
i n f o
Article history: Received 1 November 2014 Received in revised form 1 February 2015 Accepted 6 February 2015 Available online 7 February 2015 Keywords: 9p duplication syndrome Psychosis Autism
a b s t r a c t This article describes a 19-year-old female with mild facial dysmorphism, asociality, decreased school performance, and psychotic behavior in whom the karyotype showed an extra-chromosomal marker characterized as 9p24.3–9q21.11 duplication by array-CGH. The 69 Mbp duplicated segment in this patient includes the critical 9p duplication syndrome region, the GLDC and C90RF72 genes associated with psychotic behavior and other conduct disorders, and a potential locus for autism. © 2015 Elsevier B.V. All rights reserved.
1. Introduction
2. Case presentation
The 9p trisomy represents the 4th most common life-compatible autosomal trisomy and one of the most clinically characterized chromosomal abnormalities after trisomies 21, 13, and 18 (Temtamy et al., 2007; San Román Muñoz et al., 2004). Its severity correlates with the extension of the involved chromosomal segment (Temtamy et al., 2007). Craniofacial abnormalities and intellectual disability (ID) are common, but to date only one case of 9p duplication featuring autism (Abu-Amero et al., 2010) has been described in trisomy 9p. Most of the 9p duplication cases originate as meiotic unbalances in parents with balanced translocations (Haddad et al., 1996). This article describes a young female patient affected by ID, psychotic episodes, and craniofacial dysmorphism.
A 19 year-old-female patient from a rural area was attended at the Psychiatric Service of the Hospital Civil de Guadalajara (Mexico) due to an acute psychotic episode started on the day before the visit. The episode consisted of disorganized speech, auditory and visual hallucinations, mystic and persecutory delusions and disorientation. Once the medical causes were discarded, including neuroinfection and encephalitis by magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) analysis, the patient received treatment with olanzapine and valproate showing a significant improvement after the first week of therapy. There were previous psychotic episodes with full interepisode remission. The patient is referred to have poor socialization, but there are no additional symptoms. The patient is a single child from a nonconsanguineous and reportedly healthy couple. After a surveilled pregnancy, the patient was delivered by cesarean section due to acute fetal distress, and birth weight and size are not known. In addition to persistent enuresis until 7 years old, the remaining psychomotor development is unnoticeable. She started scholarity at age 4 y.o. and showed poor learning and social disabilities. Menarche happened at 10 y.o. and sexual development was normal. Physical examination showed a well oriented girl with a cooperative attitude during the interview, but psychomotor hyperreactivity and alterations in logical reasonings were noted. Patient was 1.55 cm tall and her weight was 49.5 kg, with a BMI of 20.6. The exam showed micrognathia, arched palate, bulbous nose, downturned corners of mouth, low set ears, short neck and brachymesodactyly. An umbilical hernia was also observed. The rest of
Abbreviations: Array-CGH, array based comparative genomic hybridization; BMI, body mass index; C9orf123 gene, chromosome 9 open reading frame 72; C9orf66 gene, chromosome 9 open reading frame 66; C9orf72 gene, chromosome 9 open reading frame 72; CNVs, copy number variations; DECIPHER, DatabasE of Genomic variants and Phenotype in Humans Using Ensembl Resources; DOCK8 gene, dedicator of cytokinesis 8; FOXD4 gene, forkhead box D4; GLDC gene, glycine dehydrogenase; ID, intellectual disability; KANK1 (ANKRD15) gene, KN motif and ankyrin repeat domains 1; MRI, magnetic resonance imaging; NMDA, N-methyl-D-aspartate; PTPRD gene, protein tyrosine phosphatase receptor type D; UCSC Genome Browser, University of California Santa Cruz Genome Browser. ⁎ Corresponding author at: Facultad de Medicina and Centro de Investigación y Desarrollo en Ciencias de la Salud, Universidad Autónoma de Nuevo León, Carlos Canseco S.N., Colonia Mitras Centro, Monterrey C.P. 64460, Mexico. E-mail addresses: [email protected], [email protected] (A. Rojas-Martínez).
http://dx.doi.org/10.1016/j.gene.2015.02.010 0378-1119/© 2015 Elsevier B.V. All rights reserved.
L. Martínez-Jacobo et al. / Gene 560 (2015) 124–127
the clinical examination, electroencephalogram, cardiologic evaluation, and standard cranial radiographs and MRI studies were normal. 3. Material and methods 3.1. Chromosomal analysis Before the studies, the patient's mother was informed about the genetic studies, including aCGH, and signed the consent. Initial cytogenetic analyses were performed by standard 72 h lymphocyte culture (PB-MAX, Gibco®) and G-banding on 30 metaphases, at a resolution of 450 bands approximately. An additional EDTA-anticoagulated blood sample was used for DNA isolation and aCGH studies. Parental samples for chromosome studies were not available. 3.2. Array CGH Genomic DNA (250 ng) was obtained from 3 ml of peripheral blood by Qiagen DNeasy Blood & Tissue Kit (Qiagen, Hilden, Germany), digested with restriction enzymes Sty I and Nsp I (New England BioLabs, Ipswich, MA), and ligated to Sty I or Nsp I adaptors, respectively. After PCR amplification, random fragmentation, purification and labeling procedures, samples were hybridized to Affymetrix GenomeWide SNP 6.0 arrays (Affymetrix, Santa Clara, CA) for 16–18 h in a hybridization oven. Washing and staining of the arrays were performed using the fluidics station 450 (Affymetrix); array images were acquired using the Affymetrix GeneChip Scanner 3000; Affymetrix, and analyzed by using the Genotyping Console v4.0 software. 4. Results The patient's 47,XX,+mar karyotype found in all cells was reinterpreted after molecular studies including a supernumerary marker 9pter–q21.11. The aCGH study demonstrated that the marker corresponded to a 69 Mb duplicated segment of chromosome 9 (genomic positions 46, 587-69, 186, 399), involving 31,069 markers and 280 genes (including miRNAs and hypothetic protein-genes) (NCBI36/ hg18), indicative of a partial trisomy 9pter–q21.11 (Fig. 1). The final karyotype for this patient is 47,XX,+mar.arr9p24.3q21.11 (46, 587-69, 186, 399) × 3 (Fig. 1). This duplication involves: a) the critical region for the 9p duplication syndrome, b) the GLDC gene associated with non-ketotic hyperglycinemia (NKH) (Kure et al., 1997), c) the C90RF72 gene
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associated with psychotic behavior (Galimberti et al., 2013), d) a locus associated with autism (Abu-Amero et al., 2010), and e) several genes associated with ID and to additional disturbances of conduct, like KANK1, DOCK8, FOXD4, C9orf123, and PTPRD. Similar duplications have been also reported (Lin et al., 1977; Stoll et al., 1992; Temtamy et al., 2007; Bonaglia et al., 2002; Di Bartolo et al., 2012) (Fig.2). No additional genomic disturbances were observed.
5. Discussion A patient with mild features of 9p duplication syndrome and psychotic episodes had an extra marker 9pter → q21.11 showing partial trisomy of chromosome 9. In spite of the marker chromosome's size, its identification using only G bands was not possible. Similar cases of partial trisomies of chromosome 9 in which marker chromosomes were identified by complementary techniques have been reported by Lin et al. (1977) and Temtamy et al. (2007). The proposita's karyotype showed a likely stable extra 9p marker. The marker's mitotic stability indicates that the broken end is capped with a functional telomere be it a neotelomere or captured from 9q or another chromosome. Although we did not analyze the chromosomes of the patient's parents and therefore cannot exclude a parental translocation (e.g., Teraoka et al., 2001; family 2 in Vázquez-Cárdenas et al., 2007), the family history rather supports a de novo origin as it has been documented for other extra 9p chromosomes (patient 4 in Temtamy et al., 2007; Abu-Amero et al., 2010). The region shares a duplicated segment with the 9p duplication syndrome critical region (9p22.3–9p22.2) (Abu-Amero et al., 2010), which partially explains her dysmorphic features. The clinical picture of the 9p duplication syndrome mainly includes ID, craniofacial malformations as microcephaly, micrognathia, downturned corners of the mouth among others, and distal phalangeal hypoplasia (Sirisena et al., 2013). There is only one report of autism (Abu-Amero et al., 2010) but no cases of psychotic disturbances in patients with 9p duplication. The search of related cases in DECIPHER (Firth et al., 2009) database displays 186 cases related to the duplicated segment in this patient. In addition to the physical malformations described in them, there are 20 instances of autism, 5 of psychosis, and 10 related to other psychiatric conditions, such as aggressive behavior. Among the genes involved in this duplicated region, GLDC, C9orf66, DOCK8, FOXD4, C9orf72, and KANK1 have been associated with altered neurodevelopment.
Fig. 1. (A) Patient's karyotype showing a marker chromosome. (B) Microarray image of duplicate region of chromosome 9 from Genotyping Console v.4 Software.
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Fig. 2. Reported cases with 9p imbalances overlapping the duplicated region in the present case. Vertical green lines indicate potential loci for autism. Vertical black lines indicate the critical region for the 9p duplication syndrome. ID.255468, ID.248471, ID.257283, ID.277528, ID.271336, ID.279709 and ID.287059 are cases found in the DECIPHER database.
Psychosis, as reported in this patient, was also observed in three previously reported patients with 9p imbalances involving the GLDC and KDM4C genes (Firth et al., 2009) (Fig. 3). The GLDC gene codifies glycine decarboxylase. Glycine is a well-established co-agonist
Fig. 3. Common genes identified in reported cases of 9p imbalances and psychosis/ psychiatric behavior in DECIPHER database. Red = deletions and blue = duplications. (A) Cases with psychosis. (B) Cases with psychiatric behavior.
neurotransmitter with glutamate at N-methyl-D-aspartate (NMDA) receptors (Gray and Nicoll, 2012; Nonog et al., 2003). Mutations in GLDC gene produce non-ketotic hyperglycinemia and severe neural injury (Kure et al., 1997). GLDC and KDM4C gene duplications were already reported as a CNV of uncertain significance for schizophrenia and epilepsy (Stewart et al., 2011). Kantrowitz and Javitt (2010) hypothesized that GLDC gene duplications increased glycine catabolism and NMDA receptor hypoactivity, which may be related to schizophrenic phenotype, and there are some pilot studies evaluating the administration of glycine for the treatment of psychotic patients (Kantrowitz and Javitt, 2010; Woods et al., 2013). Duplication of GLDC was also reported in a patient with seizures (Olson et al., 2014) and in three instances of familial glioblastoma (Andersson et al., 2014). C9orf66, DOCK8 and KANK1 CNVs were also found in 6/10 patients with psychiatric behavior reported in DECIPHER and this report contributes with an additional case (Fig. 3). DOCK8 and KANK1 have been associated with ID (Griggs et al., 2008; Lerer et al., 2005; Recalcati et al., 2012). C9orf66 function remains unknown (Griggs et al., 2008). Abu-Amero et al. (2010) reported a mosaic 9p duplication patient and suggested a candidate locus for autism in 9p24.3. After this report, other researchers identified a CNV probably associated with autism in the same region that involves the C9orf66, CBWD1, DOCK8 and FOXD4 genes (Pinto et al., 2010; Sanders et al., 2011). This CNV is also duplicated in the reported patient, in whom the diagnosis of autism is debatable, although her associability is remarkable. The genetics of psychiatric disorders is complex (Harris, 2010). However, with the use of modern genomic tools has been identified CNVs that confer risk to disorders like autism and schizophrenia (Stefansson et al., 2014). This genetic complexity dictates that assessment of the biomedical relevance of copy-number variants and the genes that they affect needs to be considered in an integrated context (Cook and Scherer, 2008). FOXD4, C9orf123, C9orf72 and PTPRD genes, duplicated in this patient, have been involved in behavioral disorders. For instance, FOXD4
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mutations have been associated with obsessive–compulsive disorder and suicidal behavior, as well as autism; C9orf123 ones with attention deficit and disruptive behavior disorders, and those of PTPRD with attention deficit/hyperactivity disorder. The C9orf72 gene codifies for an uncharacterized protein present in the brain tissue and a dynamic mutation of this gene consisting of hexanucleotide repeats is associated with frontotemporal dementia and psychosis (Snowden et al., 2012; Kent et al., 2002). To summarize, since duplicated genomic region in the present case contains genes related to abnormal neurodevelopment and behavior, molecular abnormalities may explain the malformed phenotype and the mental and behavioral disorders. Observations in the reported patient sustain that GLDC and C9orf72 genes could be implicated in schizophrenia and psychosis; support the involvement of 9p24.3 as a locus associated with autism (UCSC-Genome Browser); suggest that genes KANK1, DOCK8, and FOXD4 are related to autistic trait; and also support the involvement of C9orf123, PTPRD and FOXD4 in ID and behavioral disorders. 6. Conclusion This article reports a 9p duplication patient with malformations, associability and psychotic behavior. Expression of duplicated genes may explain the malformed phenotype and the mental and behavioral disorders, including psychotic traits. Acknowledgments We would like to thank the patient's mother for their cooperation along this study. Lizeth Martínez-Jacobo is supported by a CONACYT (Mexico) scholarship. References Abu-Amero, K.K., Hellani, A.M., Salih, M., Seidahmed, M.Z., Elmalik, T.S., Zidan, G., Bosley, T.M., 2010. A de novo marker chromosome derived from 9p in a patient with 9p partial duplication syndrome and autism features: genotype–phenotype correlation. BMC Med. Genet. 11, 135. http://dx.doi.org/10.1186/1471-2350-11-135. Andersson, U., Wibom, C., Cederquist, K., Aradottir, S., Borg, A., et al., 2014. Germline rearrangements in families with strong family history of glioma and malignant melanoma, colon, and breast cancer. Neuro-Oncology 1–8 http://dx.doi.org/10.1093/neuonc/ nou052. Bonaglia, M.C., Giorda, R., Carrozzo, R., Roncoroni, M.E., Grasso, R., Borgatti, R., Zuffardi, O., 2002. 20-Mb duplication of chromosome 9p in a girl with minimal physical findings and normal IQ: narrowing of the 9p duplication critical region to 6 Mb. Am. J. Med. Genet. 112 (2), 154–159. Cook, E., Scherer, S., 2008. Copy-number variations associated with neuropsychiatric conditions. Nature 455, 919–923. http://dx.doi.org/10.1038/nature07458. Di Bartolo, D.L., El Naggar, M., Owen, R., Sahoo, T., Gilbert, F., Pulijaal, V.R., Mathew, S., 2012. Characterization of a complex rearrangement involving duplication and deletion of 9p in an infant with craniofacial dysmorphism and cardiac anomalies. Mol. Cytogenet. 5, 31. http://dx.doi.org/10.1186/1755-8166-5-31. Firth, H.V., et al., 2009. DECIPHER: database of chromosomal imbalance and phenotype in humans using ensembl resources. Am. J. Hum. Genet. 84, 524–533. http://dx.doi.org/ 10.1016/j.ajhg.2009.03.010. Galimberti, D., Fenoglio, C., Serpente, M., Villa, C., Bonsi, R., et al., 2013. Autosomal dominant frontotemporal lobar degeneration due to the C9ORF72 hexanucleotide repeat expansion: late-onset psychotic clinical presentation. Biol. Psychiatry 74 (5), 384–391. http://dx.doi.org/10.1016/j.biopsych.2013.01.031. Gray, J.A., Nicoll, R.A., 2012. Thinking outside the synapse: glycine at extrasynaptic NMDA receptors. Cell 150 (3), 455–456. http://dx.doi.org/10.1016/j.cell.2012.07.013. Griggs, B.L., Ladd, S., Saul, R.A., DuPont, B.R., Srivastava, A.K., 2008. Dedicator of cytokinesis 8 is disrupted in two patients with mental retardation and developmental disabilities. Genomics 91 (2), 195–202.
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