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16q12.2q21: A new susceptibility locus for schizophrenia?
SCHRES-06960; No of Pages 3 Schizophrenia Research xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Schizophrenia Research journal homepage: www.elsevier.com/locate/schres
Letter to the Editor 16q12.2q21: A new susceptibility locus for schizophrenia? Keywords: Schizophrenia Genetics Copy number variant Microduplication Autism
Dear Editors, The genetics of psychiatric disorders is a fast-expanding field. DNA micro array analysis (molecular karyotype, array CGH) techniques being increasingly accessible, identification of schizophrenia associated to the presence of pathogenic copy number variations (CNV) is improving. For instance, it has been shown that schizophrenia is usually detected in 24–33% of patients with 22q11.2 deletion syndrome (Murphy et al., 1999). This core observation has helped detect the disease more efficiently and provide early interventions if needed. We report here the yet unknown association between schizophrenia and 16q12.2q21 duplication. The patient is a 26-year-old woman with schizophrenia. No remarkable medical or miscarriage history was reported in the family. During early childhood, she underwent a surgery for congenital nystagmus. She also suffered from long-sightedness and constipation. At the age of 3, her teacher pointed out a mild expressive speech delay and some fine motor skills difficulties. Then, a 400 bands level RHG karyotype was performed and showed a de novo structural anomaly of the short arm of chromosome 16, which could not be further characterized with the techniques available at that time. The patient grew up and went on to pursue vocational education. At the age of 19, anxiety and sadness appeared. They increased along with learning difficulties and absenteeism at school. Eventually, she presented a subacute psychomotor agitation with auditory hallucinations (she could hear Harry Potter talking). A schizophrenia was diagnosed (DSM-5 criteria). Aripiprazole (10 mg/day) was then introduced. As symptoms persisted, various antipsychotics were successively tried: haloperidol, olanzapine, loxapine, risperidone and cymemazine. They all induced motor complications at low doses (b 100 mg of chlorpromazine equivalent doses), including general dystonia and severe extrapyramidal syndrome. Picture from that period show decreased expressiveness, cervical dystonia and oromandibular dystonia (Fig. 1B). At least, the use of clozapine (75 mg/day) helped alleviate psychotic and iatrogenic motor symptoms. The patient was then referred to genetic consultation. Neurological examination disclosed a mild oromandibular dystonia, a symmetric extrapyramidal syndrome, a postural tremor and a horizontal nystagmus. Height was 178 cm (+ 2.5 SD); weight, 67 kg (+1.5 SD) and cranial perimeter, 54 cm (N). Morphologic examination revealed small ears, long and thin fingers and mild mandibular
hypoplasia (Fig. 1A, C, D, E). The rest of the clinical examination was unremarkable. Cerebral MRI, abdominal ultrasounds, and foot and fingers X-ray were normal. Neuropsychological evaluation (WAIS IV) revealed an executive dysfunction without intellectual deficiency. In sum, the patient presented with a schizophrenia characterized by treatment resistance, severe neurological side effects of medications, mild cognitive difficulties and peculiar morphological features associated to a de novo abnormality of chromosome 16 of unknown significance. Based on these observations, an array CGH was performed (Human Genome CGH microarray 180K, Agilent, Santa Clara, CA, USA). It revealed a 12.3 Mb gain in 16q12.2q21 arr[hg19] 16q12.2q21(52,651,51765,006,934)x3, confirmed by karyotype and by fluorescent in situ hybridization (FISH). The 550 bands level RHG and GTG karyotype disclosed a duplication of the long arm of one chromosome 16 and an apparently balanced reciprocal translocation between the short arm of one chromosome 2 and the short arm of the other chromosome 16 46,XX,t(2;16)(p23;p13.1),dup(16)(q12.2q21). The FISH confirmed these results. Parental studies demonstrated that 16q12.2q21 duplication arose de novo and that the balanced t(2;16) translocation was inherited from her father. In conclusion, the patient presented with two independent chromosomal rearrangements involving both chromosomes 16, a paternally inherited balanced reciprocal translocation of the short arm and a 16q12.2q21 de novo duplication, the latter providing an explanation for the patient's phenotype. Isolated proximal-intermediate duplications of 16q, involving 16q11.2 to q22 bands, have been rarely reported. Common phenotypic traits consisted in intellectual disability, developmental and speech delay, obesity, strabism, anisomasties, mild squeletal abnomalies and behavioural problems (Romain et al., 1984, Mariner et al., 1986, Fryns et al., 1990, Engelen et al., 1999, Barber et al., 2006, Lonardo et al., 2011, Odak et al., 2011). Wider duplications might be associated to lumbosacral myelomeningocele, Arnold Chiari type 2 malformation, epileptic seizures and visual impairment (Gustavsson et al., 2007). Behavioural problems included attention deficit hyperactivity disorder, aggressiveness and autistic spectrum disorder. Interestingly, this is the first report of schizophrenia without intellectual deficiency associated to a 16q12.2q21 duplication. To the best of our knowledge, this locus was never reported to be associated with schizophrenia. Thus, patients carrying 16q12.2q21 duplication might benefit, as 22q11 deletion patients do, from a regular psychiatric evaluation. Last but not least, this observation highlights the possible role of psychotropic medications in inducing severe side effects in some genetic syndromes. On one hand, this means that the use of these treatments in known genetic syndromes requires monitoring of neurological side-effect and the use of clozapine if necessary (Verhoeven and Egger, 2015). On the other hand, it suggests that intolerance and resistance to psychotropic medications might be red flags for syndromic schizophrenia.
Conflict of interest The authors declare that they have no conflict of interest.
http://dx.doi.org/10.1016/j.schres.2016.09.007 0920-9964/© 2016 Published by Elsevier B.V.
Please cite this article as: Poisson, A., et al., 16q12.2q21: A new susceptibility locus for schizophrenia?, Schizophr. Res. (2016), http://dx.doi.org/ 10.1016/j.schres.2016.09.007
2
Letter to the Editor
Fig. 1. Morphological aspect the patient with 16q12.2q21 deletion at the age of 9 (A) and 26 (B, C, D, E).
Contributors AP wrote the first draft of the manuscript. CSB and DS were in charge of the cytogenetic analyses. MNB helped to draft some subsection of the manuscript. CSB, DS, BM and CD have revised the manuscript critically for intellectual content. All authors read and approved the final manuscript.
Acknowledgment The authors would like to thank Mr. Gilles Collot for English editing and the Vinatier Hospital for its support.
References Barber, J.C., Zhang, S., Friend, N., Collins, A.L., Maloney, V.K., Hastings, R., Farren, B., Barnicoat, A., Polityko, A.D., Rumyantseva, N.V., Starke, H., Ye, S., 2006. Duplications of proximal 16q flanked by heterochromatin are not euchromatic variants and show no evidence of heterochromatic position effect. Cytogenet. Genome Res. 114 (3–4), 351–358. Engelen, J.J., De Die-Smulders, C.E., Vos, P.T., Meers, L.E., Albrechts, J.C., Hamers, A.J., 1999. Characterization of a partial trisomy 16q with FISH. Report of a patient and review of the literature. Ann. Genet. 42 (2), 101–104. Fryns, J.P., Kleczkowska, A., Decock, P., Van den Berghe, H., 1990. Direct duplication 16q11.1——16q13 is not associated with a typical dysmorphic syndrome. Ann. Genet. 33 (1), 46–48. Gustavsson, P., Schoumans, J., Staaf, J., Borg, A., Nordenskjöld, M., Annerén, G., 2007. Duplication 16q12.1-q22.1 characterized by array CGH in a girl with spina bifida. Eur. J. Med. Genet. 50 (3), 237–241. Lonardo, F., Perone, L., Maioli, M., Ciavarella, M., Ciccone, R., Monica, M.D., Lombardi, C., Forino, L., Cantalupo, G., Masella, L., Scarano, F., 2011. Clinical, cytogenetic and molecular-cytogenetic characterization of a patient with a de novo tandem proximal-intermediate duplication of 16q and review of the literature. Am. J. Med. Genet. A 155A (4), 769–777. Mariner, R., Jackson, A.W., Levitas, A., Hagerman, R.J., Braden, M., McBogg, P.M., Smith, A.C., Berry, R., 1986. Autism, mental retardation, and chromosomal abnormalities. J. Autism Dev. Disord. 16 (4), 425–440. Murphy, K.C., Jones, L.A., Owen, M.J., 1999. High rates of schizophrenia in adults with Velo-cardio-facial syndrome. Arch. Gen. Psychiatry 56 (10), 940–945. Odak, L., Barisic, I., Morozin Pohovski, L., Riegel, M., Schinzel, A., 2011. Novel duplication on chromosome 16(q12.1q21) associated with behavioural disorder, mild cognitive impairment, speech delay, and dysmorphic features:case report. Croat. Med. J. 52 (3), 415–422.
Romain, D.R., Frazer, A.G., Columbano-Green, L.M., Parfitt, R.G., Smythe, R.H., Chapman, C.J., 1984. Direct intrachromosomal duplication of 16q and heritable fragile site fra (10) (q25) in the same patient. Am. J. Med. Genet. 19 (3), 507–513. Verhoeven, W.M., Egger, J.I., 2015. Atypical antipsychotics and relapsing psychoses in 22q11.2 deletion syndrome: a long-term evaluation of 28 patients. Pharmacopsychiatry 48 (3), 104–110.
A. Poisson⁎ GénoPsy, Center for Diagnosis and management of genetic psychiatric disorders, Centre Hospitalier le Vinatier and EDR-Psy team (CNRS & Lyon 1 Claude Bernard University), Lyon, France Corresponding author at: Génopsy, Pôle ouest, CH le Vinatier, 59 Bd Pinel, 69678 Bron, France. E-mail address: [email protected]. C. Schluth Bolard HCL, Department of Genetics, Reference Center for Developmental Anomalies and Malformation Syndromes, Bron, France GENDEV, Centre de Recherche en Neurosciences de Lyon, INSERM U1028, CNRS UMR529, UCBL1, Lyon, France B. Martin SUR/CL3R, UMR 5229 (CNRS & Lyon 1 University) CH le Vinatier, Bron, France M.N. Babinet GénoPsy, Center for Diagnosis and management of genetic psychiatric disorders, Centre Hospitalier le Vinatier and EDR-Psy team (CNRS & Lyon 1 Claude Bernard University), Lyon, France D. Sanlaville HCL, Department of Genetics, Reference Center for Developmental Anomalies and Malformation Syndromes, Bron, France GENDEV, Centre de Recherche en Neurosciences de Lyon, INSERM U1028, CNRS UMR529, UCBL1, Lyon, France
Please cite this article as: Poisson, A., et al., 16q12.2q21: A new susceptibility locus for schizophrenia?, Schizophr. Res. (2016), http://dx.doi.org/ 10.1016/j.schres.2016.09.007
Letter to the Editor
C. Demily GénoPsy, Center for Diagnosis and management of genetic psychiatric disorders, Centre Hospitalier le Vinatier and EDR-Psy team (CNRS & Lyon 1 Claude Bernard University), Lyon, France 9 June 2016 Available online xxxx
Please cite this article as: Poisson, A., et al., 16q12.2q21: A new susceptibility locus for schizophrenia?, Schizophr. Res. (2016), http://dx.doi.org/ 10.1016/j.schres.2016.09.007
3
Contents lists available at ScienceDirect
Schizophrenia Research journal homepage: www.elsevier.com/locate/schres
Letter to the Editor 16q12.2q21: A new susceptibility locus for schizophrenia? Keywords: Schizophrenia Genetics Copy number variant Microduplication Autism
Dear Editors, The genetics of psychiatric disorders is a fast-expanding field. DNA micro array analysis (molecular karyotype, array CGH) techniques being increasingly accessible, identification of schizophrenia associated to the presence of pathogenic copy number variations (CNV) is improving. For instance, it has been shown that schizophrenia is usually detected in 24–33% of patients with 22q11.2 deletion syndrome (Murphy et al., 1999). This core observation has helped detect the disease more efficiently and provide early interventions if needed. We report here the yet unknown association between schizophrenia and 16q12.2q21 duplication. The patient is a 26-year-old woman with schizophrenia. No remarkable medical or miscarriage history was reported in the family. During early childhood, she underwent a surgery for congenital nystagmus. She also suffered from long-sightedness and constipation. At the age of 3, her teacher pointed out a mild expressive speech delay and some fine motor skills difficulties. Then, a 400 bands level RHG karyotype was performed and showed a de novo structural anomaly of the short arm of chromosome 16, which could not be further characterized with the techniques available at that time. The patient grew up and went on to pursue vocational education. At the age of 19, anxiety and sadness appeared. They increased along with learning difficulties and absenteeism at school. Eventually, she presented a subacute psychomotor agitation with auditory hallucinations (she could hear Harry Potter talking). A schizophrenia was diagnosed (DSM-5 criteria). Aripiprazole (10 mg/day) was then introduced. As symptoms persisted, various antipsychotics were successively tried: haloperidol, olanzapine, loxapine, risperidone and cymemazine. They all induced motor complications at low doses (b 100 mg of chlorpromazine equivalent doses), including general dystonia and severe extrapyramidal syndrome. Picture from that period show decreased expressiveness, cervical dystonia and oromandibular dystonia (Fig. 1B). At least, the use of clozapine (75 mg/day) helped alleviate psychotic and iatrogenic motor symptoms. The patient was then referred to genetic consultation. Neurological examination disclosed a mild oromandibular dystonia, a symmetric extrapyramidal syndrome, a postural tremor and a horizontal nystagmus. Height was 178 cm (+ 2.5 SD); weight, 67 kg (+1.5 SD) and cranial perimeter, 54 cm (N). Morphologic examination revealed small ears, long and thin fingers and mild mandibular
hypoplasia (Fig. 1A, C, D, E). The rest of the clinical examination was unremarkable. Cerebral MRI, abdominal ultrasounds, and foot and fingers X-ray were normal. Neuropsychological evaluation (WAIS IV) revealed an executive dysfunction without intellectual deficiency. In sum, the patient presented with a schizophrenia characterized by treatment resistance, severe neurological side effects of medications, mild cognitive difficulties and peculiar morphological features associated to a de novo abnormality of chromosome 16 of unknown significance. Based on these observations, an array CGH was performed (Human Genome CGH microarray 180K, Agilent, Santa Clara, CA, USA). It revealed a 12.3 Mb gain in 16q12.2q21 arr[hg19] 16q12.2q21(52,651,51765,006,934)x3, confirmed by karyotype and by fluorescent in situ hybridization (FISH). The 550 bands level RHG and GTG karyotype disclosed a duplication of the long arm of one chromosome 16 and an apparently balanced reciprocal translocation between the short arm of one chromosome 2 and the short arm of the other chromosome 16 46,XX,t(2;16)(p23;p13.1),dup(16)(q12.2q21). The FISH confirmed these results. Parental studies demonstrated that 16q12.2q21 duplication arose de novo and that the balanced t(2;16) translocation was inherited from her father. In conclusion, the patient presented with two independent chromosomal rearrangements involving both chromosomes 16, a paternally inherited balanced reciprocal translocation of the short arm and a 16q12.2q21 de novo duplication, the latter providing an explanation for the patient's phenotype. Isolated proximal-intermediate duplications of 16q, involving 16q11.2 to q22 bands, have been rarely reported. Common phenotypic traits consisted in intellectual disability, developmental and speech delay, obesity, strabism, anisomasties, mild squeletal abnomalies and behavioural problems (Romain et al., 1984, Mariner et al., 1986, Fryns et al., 1990, Engelen et al., 1999, Barber et al., 2006, Lonardo et al., 2011, Odak et al., 2011). Wider duplications might be associated to lumbosacral myelomeningocele, Arnold Chiari type 2 malformation, epileptic seizures and visual impairment (Gustavsson et al., 2007). Behavioural problems included attention deficit hyperactivity disorder, aggressiveness and autistic spectrum disorder. Interestingly, this is the first report of schizophrenia without intellectual deficiency associated to a 16q12.2q21 duplication. To the best of our knowledge, this locus was never reported to be associated with schizophrenia. Thus, patients carrying 16q12.2q21 duplication might benefit, as 22q11 deletion patients do, from a regular psychiatric evaluation. Last but not least, this observation highlights the possible role of psychotropic medications in inducing severe side effects in some genetic syndromes. On one hand, this means that the use of these treatments in known genetic syndromes requires monitoring of neurological side-effect and the use of clozapine if necessary (Verhoeven and Egger, 2015). On the other hand, it suggests that intolerance and resistance to psychotropic medications might be red flags for syndromic schizophrenia.
Conflict of interest The authors declare that they have no conflict of interest.
http://dx.doi.org/10.1016/j.schres.2016.09.007 0920-9964/© 2016 Published by Elsevier B.V.
Please cite this article as: Poisson, A., et al., 16q12.2q21: A new susceptibility locus for schizophrenia?, Schizophr. Res. (2016), http://dx.doi.org/ 10.1016/j.schres.2016.09.007
2
Letter to the Editor
Fig. 1. Morphological aspect the patient with 16q12.2q21 deletion at the age of 9 (A) and 26 (B, C, D, E).
Contributors AP wrote the first draft of the manuscript. CSB and DS were in charge of the cytogenetic analyses. MNB helped to draft some subsection of the manuscript. CSB, DS, BM and CD have revised the manuscript critically for intellectual content. All authors read and approved the final manuscript.
Acknowledgment The authors would like to thank Mr. Gilles Collot for English editing and the Vinatier Hospital for its support.
References Barber, J.C., Zhang, S., Friend, N., Collins, A.L., Maloney, V.K., Hastings, R., Farren, B., Barnicoat, A., Polityko, A.D., Rumyantseva, N.V., Starke, H., Ye, S., 2006. Duplications of proximal 16q flanked by heterochromatin are not euchromatic variants and show no evidence of heterochromatic position effect. Cytogenet. Genome Res. 114 (3–4), 351–358. Engelen, J.J., De Die-Smulders, C.E., Vos, P.T., Meers, L.E., Albrechts, J.C., Hamers, A.J., 1999. Characterization of a partial trisomy 16q with FISH. Report of a patient and review of the literature. Ann. Genet. 42 (2), 101–104. Fryns, J.P., Kleczkowska, A., Decock, P., Van den Berghe, H., 1990. Direct duplication 16q11.1——16q13 is not associated with a typical dysmorphic syndrome. Ann. Genet. 33 (1), 46–48. Gustavsson, P., Schoumans, J., Staaf, J., Borg, A., Nordenskjöld, M., Annerén, G., 2007. Duplication 16q12.1-q22.1 characterized by array CGH in a girl with spina bifida. Eur. J. Med. Genet. 50 (3), 237–241. Lonardo, F., Perone, L., Maioli, M., Ciavarella, M., Ciccone, R., Monica, M.D., Lombardi, C., Forino, L., Cantalupo, G., Masella, L., Scarano, F., 2011. Clinical, cytogenetic and molecular-cytogenetic characterization of a patient with a de novo tandem proximal-intermediate duplication of 16q and review of the literature. Am. J. Med. Genet. A 155A (4), 769–777. Mariner, R., Jackson, A.W., Levitas, A., Hagerman, R.J., Braden, M., McBogg, P.M., Smith, A.C., Berry, R., 1986. Autism, mental retardation, and chromosomal abnormalities. J. Autism Dev. Disord. 16 (4), 425–440. Murphy, K.C., Jones, L.A., Owen, M.J., 1999. High rates of schizophrenia in adults with Velo-cardio-facial syndrome. Arch. Gen. Psychiatry 56 (10), 940–945. Odak, L., Barisic, I., Morozin Pohovski, L., Riegel, M., Schinzel, A., 2011. Novel duplication on chromosome 16(q12.1q21) associated with behavioural disorder, mild cognitive impairment, speech delay, and dysmorphic features:case report. Croat. Med. J. 52 (3), 415–422.
Romain, D.R., Frazer, A.G., Columbano-Green, L.M., Parfitt, R.G., Smythe, R.H., Chapman, C.J., 1984. Direct intrachromosomal duplication of 16q and heritable fragile site fra (10) (q25) in the same patient. Am. J. Med. Genet. 19 (3), 507–513. Verhoeven, W.M., Egger, J.I., 2015. Atypical antipsychotics and relapsing psychoses in 22q11.2 deletion syndrome: a long-term evaluation of 28 patients. Pharmacopsychiatry 48 (3), 104–110.
A. Poisson⁎ GénoPsy, Center for Diagnosis and management of genetic psychiatric disorders, Centre Hospitalier le Vinatier and EDR-Psy team (CNRS & Lyon 1 Claude Bernard University), Lyon, France Corresponding author at: Génopsy, Pôle ouest, CH le Vinatier, 59 Bd Pinel, 69678 Bron, France. E-mail address: [email protected]. C. Schluth Bolard HCL, Department of Genetics, Reference Center for Developmental Anomalies and Malformation Syndromes, Bron, France GENDEV, Centre de Recherche en Neurosciences de Lyon, INSERM U1028, CNRS UMR529, UCBL1, Lyon, France B. Martin SUR/CL3R, UMR 5229 (CNRS & Lyon 1 University) CH le Vinatier, Bron, France M.N. Babinet GénoPsy, Center for Diagnosis and management of genetic psychiatric disorders, Centre Hospitalier le Vinatier and EDR-Psy team (CNRS & Lyon 1 Claude Bernard University), Lyon, France D. Sanlaville HCL, Department of Genetics, Reference Center for Developmental Anomalies and Malformation Syndromes, Bron, France GENDEV, Centre de Recherche en Neurosciences de Lyon, INSERM U1028, CNRS UMR529, UCBL1, Lyon, France
Please cite this article as: Poisson, A., et al., 16q12.2q21: A new susceptibility locus for schizophrenia?, Schizophr. Res. (2016), http://dx.doi.org/ 10.1016/j.schres.2016.09.007
Letter to the Editor
C. Demily GénoPsy, Center for Diagnosis and management of genetic psychiatric disorders, Centre Hospitalier le Vinatier and EDR-Psy team (CNRS & Lyon 1 Claude Bernard University), Lyon, France 9 June 2016 Available online xxxx
Please cite this article as: Poisson, A., et al., 16q12.2q21: A new susceptibility locus for schizophrenia?, Schizophr. Res. (2016), http://dx.doi.org/ 10.1016/j.schres.2016.09.007
3