- Email: [email protected]
CTNND2 deletion and intellectual disability
Gene 565 (2015) 146–149
Contents lists available at ScienceDirect
Gene journal homepage: www.elsevier.com/locate/gene
Short communication
CTNND2 deletion and intellectual disability Chiara Belcaro a,⁎, Savina Dipresa a, Giovanna Morini b, Vanna Pecile b, Aldo Skabar b, Antonella Fabretto b a b
Department of Medical Sciences, University of Trieste, Italy Institute for Maternal and Child Health — IRCCS “Burlo Garofolo”, Trieste, Italy
a r t i c l e
i n f o
Article history: Received 25 November 2014 Received in revised form 20 March 2015 Accepted 24 March 2015 Available online 1 April 2015 Keywords: CTNND2 Deletion Intellectual Disability CNV
a b s t r a c t Neurodevelopmental disorders are a group of diseases characterized by either structural or functional alterations. The clinical spectrum can vary from isolated intellectual disability to more complex syndromes. Molecular karyotyping can explain 14%–18% of cases due to the presence of large pathogenic CNVs. Moreover, small CNVs involving single genes might result in a monogenic disease. In this article we report two cases of intragenic CTNND2 deletion, detected by molecular karyotyping, in patients with isolated intellectual disability. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Neurodevelopmental disorders (NDDs) are a group of diseases characterized by either structural or functional alterations. NDD can manifest with a broad clinic spectrum, ranging from non-syndromic intellectual disability (ID) to syndromic ID, epilepsy, autism, language delay, and delayed psychomotor development (Lee and Lupski, 2006). Genetic diagnosis can be very difficult because a large amount of genes is involved in the neuronal system development. In patients with idiopathic NDD genome-wide chromosomal microarray analysis (CMA), this is the first diagnostic step (Asadollahi et al., 2014). With molecular karyotyping it is possible to explain 14%–18% of cases of NDD due to genomic gain or loss (Hochstenbach et al., 2011; Gandin et al., 2014). Copy number variants (CNVs) are an important source of genetic variation in humans (Alkan et al., 2011) and they play an important role in the development of several NDDs. The pathogenic role of large CNVs is well known. However, it is more difficult to define the pathogenic role for CNVs smaller than 500 kb (Asadollahi et al., 2014). Small CNVs can involve single genes and therefore result in a monogenic disease. Here, we describe two ID cases, positive for the presence of a small CNV (i.e. intragenic CTNND2 gene deletion), further expanding the spectrum and therefore our knowledge about CTNND2-related ID. CTNND2 gene encodes for a δ-catenin, it contains 23 exons and spans at least 640 kb (http://omim.org/entry/
Abbreviations: ID, Intellectual disability; NDD, Neurodevelopmental disorder; CNV, Copy number variation; CMA, Chromosomal microarray analysis; Chr, Chromosome. ⁎ Corresponding author at: S.C. di Genetica Medica, I.R.C.C.S. “Burlo Garofolo”, Via dell'Istria 65/1, 34137 Trieste, Italy. E-mail address: [email protected] (C. Belcaro).
http://dx.doi.org/10.1016/j.gene.2015.03.054 0378-1119/© 2015 Elsevier B.V. All rights reserved.
604275). CTNND2 gene maps in 5p15.2 region, and it is involved in the regulation of the neuronal migration and functionality of dendrites in mature cortex (Asadollahi et al., 2014). This gene has been already associated with developmental delay in Cri du Chat Syndrome and in an isolated form due to intragenic deletion (Asadollahi et al., 2014; Medina et al., 2000). 2. Methods 2.1. Patients Patient 1 was born through cesarean section at 36 weeks of gestation for breech presentation and reduced fetal movement. Parameters at birth were normal and no complications had been reported. Growth parameters were within normal limits and a physical examination did not show any particular dysmorphic feature. The presence of delayed developmental milestones was reported: he seated at 12 months of age, he walked at 18 months of age and he spoke at 2 years of age. At 6 years of age he underwent formal developmental testing and he was diagnosed with mild intellectual disability (WPPSI-III Total IQ = 70, Performance IQ = 85, Verbal IQ = 60), showing a dissociated cognitive profile with less compromised non-verbal functions rather than language. The MRI was normal, while the EEG showed an epileptic pattern in the form of rolandic spikes during sleep, without seizures reported in the medical history. The family history was negative for ID or delayed developmental milestones. Patient 2 was born spontaneously at term without any complication. Growth parameters were within normal limits. He showed delayed developmental milestones: he seated at 17 months of age and he walked at 23 months of age. He said his first words at approximately
C. Belcaro et al. / Gene 565 (2015) 146–149
147
Fig. 1. Patient 1 has a 39 kb, intronic deletion (chr5:11,422,171-11,461,920).
12 months of age. Physical examination did not show any particular dysmorphic feature. At the age of 2 he underwent a formal developmental testing, resulting in a diagnosis of mild psychomotor retardation (Bayley-III Total IQ: 60), with language skills (Verbal IQ: 83) better than non-verbal functions (Performance IQ: 53). The cognitive profile at 23 months of age was comparable to the one of a 12-month old child. EEG was normal, no seizures were
reported and MRI was not performed due to parental choice. His sister walked at 16 months of age and showed speech delay. At the moment she presents with emotional immaturity and coordination problems. His mother walked at 17 months, but she referred she spoke at a normal age. The mother's sister has a daughter who was referred to walk late, and at the age of four she did not speak properly.
Fig. 2. Patient 2 has 27,6 kb deletion involving exon 14 (chr5:11,322,037-11,349,674).
148
C. Belcaro et al. / Gene 565 (2015) 146–149
Autism, learning difficulties, mild intellectual disability Mild intellectual disability, autism, hypotonia, nasal speech
Ataxic cerebral palsy
Male 154 kb, exon 3 out-of-frame (chr5:11432332–11587173)
Male 479 kb, exons 1-3 + 5′UTR, out-of-frame (chr5:11505316–11985200) Maternal (no specific feature) Female 413 kb, exons 2–8 out-of-frame (chr5:11349694–11763030) Paternal (poor attention) Gender Deletion
Male Male NA Female 39 kb, intronic 27,6 kb, exon 14 93 kb, exons 4–9 in frame 113 kb, exons 4–7 (chr5:11,422,171-11,461,920) (chr5:11,322,037-11,349,674) (chr5:11398907–11491980) out-of-frame (chr5:11431816–11545236) De novo De novo Inheritance De novo Maternal (delayed psychomotor development milestones) NA WISC-IV IQ:77 with better Bayley-III IQ: 60 with better IQ WPPSI-III IQ:70, with better language than non-verbal language than non-verbal performance than verbal functions functions functions Autism Short attention span, Delayed developmental Neurological Delayed developmental borderline intellectual milestones, mild intellectual manifestation milestones, mild intellectual disability, memory disability disability impairment
Maternal (low normal intelligence)
Patient 7 (decipher 271234) Patient 6 (decipher 269928) Patient 5 (decipher 248402) Patient 4 (decipher 284528) Patient 3 (Girirajan et al., 2013) Patient 2 Patient 1 Patient
Table 1 Summary of all patients with CTNND2 intragenic deletion.
2.2. Molecular karyotyping Molecular karyotyping analysis was performed on our patients and also on both parents to evaluate CNV parental origin. SNP array analysis, from DNA isolated from peripheral blood lymphocytes, was carried out using the Illumina HumanOmniExpress genotyping microarray, according to the supplier protocol. Data analysis was performed using the Illumina GenomeStudio v.2011.1 software and PennCNV. 3. Results As shown in Fig. 1, patient 1 showed a 39 kb de novo deletion encompassing an intronic sequence of CTNND2 gene (chr5: 11,422,171-11,461,920). His mother presented a duplication of 350 kb in a region near the one involved in the proband (chr5: 10,798,22111,149,808). Nothing has been found in his father. Patient 2 presented a 27,6 kb inherited deletion encompassing exon 14 of CTNND2 gene (chr5: 11,322,037-11,349,674) (Fig. 2). The patient inherited this deletion from his mother. Nothing has been found in his father. 4. Discussion Cri du Chat Syndrome is a well-defined condition in which patients with a large deletion, including CTNND2 gene, have severe mental retardation, while patients with a smaller deletion, not involving CTNND2, are mentally normal or have only a mild intellectual disability (Medina et al., 2000). This aspect confirms the importance of this gene for brain function and development, and it represents an important step in the comprehension of the role of CTNND2 in the nervous system. Very recently, Asdollahi et al. described five patients with intragenic CTNND2 deletion (Table 1). In their review they considered rare exonic CNVs sizing 1–500 kb. The patients previously described presented deletions ranging from 93 kb to 479 kb, therefore larger than those described here. Authors portrayed de novo deletions, inherited deletions from a healthy parent and inherited deletions from a parent with mild intellectual disability (Asadollahi et al., 2014). The phenotypic spectrum is characterized by an autistic spectrum disorder, isolated intellectual disability, and poor attention span. In one case cerebral palsy was present. CTNND2 deletions are not described in normal population databases and this finding supports the idea that CTNND2 deletion has a pathogenic role in some neurodevelopmental disorders with a haploinsufficiency mechanism. Both patients present neurologic involvement that is consistent with the phenotype described in other cases with CTNND2 deletion because of the isolated mild intellectual disability. Patient 1's EEG presented an epileptic pattern in the form of rolandic spikes during sleep without seizures, although this pattern characterizes about 2% of the general pediatric population (Capdevila et al., 2008), being frequently associated with learning disabilities (Cavazzuti et al., 1980). The mothers of the probands both reported having a normal neurological development, although the mother of patient 2, who presented the same deletion, reported delayed walking. Unfortunately, we couldn't perform the array analysis on the sister's DNA because the mother preferred not to investigate further at that time. To better understand the role of the CTNND2 gene in the brain development, we should record that δ-catenin has a crucial role in synaptic functions and plasticity, and this has been demonstrated in mice with targeted disruption of the gene encoding δ-catenin (Kosik et al., 2005). Another evidence of the importance of δ-catenin in the brain's function is the different phenotypes in Cri du Chat Syndrome, whether or not the gene is involved in the deletion. Other researches show that the deletion of CTNND2 is also associated with autism, whereas duplication of this gene is associated with schizophrenia (McMichael et al., 2014). Moreover, CTNND2 has been recently related to other neurological disorders such as Alzheimer's disease, cortical cataract, myopia and
C. Belcaro et al. / Gene 565 (2015) 146–149
also cancer (Nopparat et al., 2015; Jun et al., 2012; Yu et al., 2012). A broad clinical spectrum comes to light from the cases described so far. Probably there are other genetic and environmental factors that contribute to define clinical phenotype. More efforts are needed in order to better understand the δ-catenin role in the pathogenesis of intellectual disability and other neurodevelopmental disorders, but by now the essential involvement of CTNND2 in brain functions is clear. References Alkan, C., Coe, B.P., Eichler, E.E., 2011. Genome structural variation discovery and genotyping. Nat. Rev. Genet. 12 (5), 363–376. Asadollahi, R., et al., 2014. The clinical significance of small copy number variants in neurodevelopmental disorders. J. Med. Genet. 51 (10), 677–688. Capdevila, O.S., et al., 2008. Prevalence of epileptiform activity in healthy children during sleep. Sleep Med. 9 (3), 303–309. Cavazzuti, G.B., Cappella, L., Nalin, A., 1980. Longitudinal study of epileptiform EEG patterns in normal children. Epilepsia 21 (1), 43–55. Gandin, I., et al., 2014. Excess of runs of homozygosity is associated with severe cognitive impairment in intellectual disability. Genet. Med. Girirajan, S., Dennis, M.Y., Baker, C., Malig, M., Coe, B.P., Campbell, C.D., et al., 2013. Refinement and discovery of new hotspots of copy-number variationassociated with autism spectrum disorder. Am. J. Hum. Genet. 92, 221–237.
149
Hochstenbach, R., et al., 2011. Genome arrays for the detection of copy number variations in idiopathic mental retardation, idiopathic generalized epilepsy and neuropsychiatric disorders: lessons for diagnostic workflow and research. Cytogenet. Genome Res. 135 (3–4), 174–202. http://omim.org/entry/604275; OMIM Database. Jun, G., et al., 2012. delta-Catenin is genetically and biologically associated with cortical cataract and future Alzheimer-related structural and functional brain changes. PLoS One 7 (9), e43728. Kosik, K.S., et al., 2005. Delta-catenin at the synaptic-adherens junction. Trends Cell Biol. 15 (3), 172–178. Lee, J.A., Lupski, J.R., 2006. Genomic rearrangements and gene copy-number alterations as a cause of nervous system disorders. Neuron 52 (1), 103–121. McMichael, G., et al., 2014. Rare copy number variation in cerebral palsy. Eur. J. Hum. Genet. 22 (1), 40–45. Medina, M., et al., 2000. Hemizygosity of delta-catenin (CTNND2) is associated with severe mental retardation in cri-du-chat syndrome. Genomics 63 (2), 157–164. Nopparat, J., et al., 2015. delta-Catenin, a Wnt/beta-catenin modulator, reveals inducible mutagenesis promoting cancer cell survival adaptation and metabolic reprogramming. Oncogene 34 (12), 1542–1552. Yu, Z., et al., 2012. Polymorphisms in the CTNND2 gene and 11q24.1 genomic region are associated with pathological myopia in a Chinese population. Ophthalmologica 228 (2), 123–129.
Contents lists available at ScienceDirect
Gene journal homepage: www.elsevier.com/locate/gene
Short communication
CTNND2 deletion and intellectual disability Chiara Belcaro a,⁎, Savina Dipresa a, Giovanna Morini b, Vanna Pecile b, Aldo Skabar b, Antonella Fabretto b a b
Department of Medical Sciences, University of Trieste, Italy Institute for Maternal and Child Health — IRCCS “Burlo Garofolo”, Trieste, Italy
a r t i c l e
i n f o
Article history: Received 25 November 2014 Received in revised form 20 March 2015 Accepted 24 March 2015 Available online 1 April 2015 Keywords: CTNND2 Deletion Intellectual Disability CNV
a b s t r a c t Neurodevelopmental disorders are a group of diseases characterized by either structural or functional alterations. The clinical spectrum can vary from isolated intellectual disability to more complex syndromes. Molecular karyotyping can explain 14%–18% of cases due to the presence of large pathogenic CNVs. Moreover, small CNVs involving single genes might result in a monogenic disease. In this article we report two cases of intragenic CTNND2 deletion, detected by molecular karyotyping, in patients with isolated intellectual disability. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Neurodevelopmental disorders (NDDs) are a group of diseases characterized by either structural or functional alterations. NDD can manifest with a broad clinic spectrum, ranging from non-syndromic intellectual disability (ID) to syndromic ID, epilepsy, autism, language delay, and delayed psychomotor development (Lee and Lupski, 2006). Genetic diagnosis can be very difficult because a large amount of genes is involved in the neuronal system development. In patients with idiopathic NDD genome-wide chromosomal microarray analysis (CMA), this is the first diagnostic step (Asadollahi et al., 2014). With molecular karyotyping it is possible to explain 14%–18% of cases of NDD due to genomic gain or loss (Hochstenbach et al., 2011; Gandin et al., 2014). Copy number variants (CNVs) are an important source of genetic variation in humans (Alkan et al., 2011) and they play an important role in the development of several NDDs. The pathogenic role of large CNVs is well known. However, it is more difficult to define the pathogenic role for CNVs smaller than 500 kb (Asadollahi et al., 2014). Small CNVs can involve single genes and therefore result in a monogenic disease. Here, we describe two ID cases, positive for the presence of a small CNV (i.e. intragenic CTNND2 gene deletion), further expanding the spectrum and therefore our knowledge about CTNND2-related ID. CTNND2 gene encodes for a δ-catenin, it contains 23 exons and spans at least 640 kb (http://omim.org/entry/
Abbreviations: ID, Intellectual disability; NDD, Neurodevelopmental disorder; CNV, Copy number variation; CMA, Chromosomal microarray analysis; Chr, Chromosome. ⁎ Corresponding author at: S.C. di Genetica Medica, I.R.C.C.S. “Burlo Garofolo”, Via dell'Istria 65/1, 34137 Trieste, Italy. E-mail address: [email protected] (C. Belcaro).
http://dx.doi.org/10.1016/j.gene.2015.03.054 0378-1119/© 2015 Elsevier B.V. All rights reserved.
604275). CTNND2 gene maps in 5p15.2 region, and it is involved in the regulation of the neuronal migration and functionality of dendrites in mature cortex (Asadollahi et al., 2014). This gene has been already associated with developmental delay in Cri du Chat Syndrome and in an isolated form due to intragenic deletion (Asadollahi et al., 2014; Medina et al., 2000). 2. Methods 2.1. Patients Patient 1 was born through cesarean section at 36 weeks of gestation for breech presentation and reduced fetal movement. Parameters at birth were normal and no complications had been reported. Growth parameters were within normal limits and a physical examination did not show any particular dysmorphic feature. The presence of delayed developmental milestones was reported: he seated at 12 months of age, he walked at 18 months of age and he spoke at 2 years of age. At 6 years of age he underwent formal developmental testing and he was diagnosed with mild intellectual disability (WPPSI-III Total IQ = 70, Performance IQ = 85, Verbal IQ = 60), showing a dissociated cognitive profile with less compromised non-verbal functions rather than language. The MRI was normal, while the EEG showed an epileptic pattern in the form of rolandic spikes during sleep, without seizures reported in the medical history. The family history was negative for ID or delayed developmental milestones. Patient 2 was born spontaneously at term without any complication. Growth parameters were within normal limits. He showed delayed developmental milestones: he seated at 17 months of age and he walked at 23 months of age. He said his first words at approximately
C. Belcaro et al. / Gene 565 (2015) 146–149
147
Fig. 1. Patient 1 has a 39 kb, intronic deletion (chr5:11,422,171-11,461,920).
12 months of age. Physical examination did not show any particular dysmorphic feature. At the age of 2 he underwent a formal developmental testing, resulting in a diagnosis of mild psychomotor retardation (Bayley-III Total IQ: 60), with language skills (Verbal IQ: 83) better than non-verbal functions (Performance IQ: 53). The cognitive profile at 23 months of age was comparable to the one of a 12-month old child. EEG was normal, no seizures were
reported and MRI was not performed due to parental choice. His sister walked at 16 months of age and showed speech delay. At the moment she presents with emotional immaturity and coordination problems. His mother walked at 17 months, but she referred she spoke at a normal age. The mother's sister has a daughter who was referred to walk late, and at the age of four she did not speak properly.
Fig. 2. Patient 2 has 27,6 kb deletion involving exon 14 (chr5:11,322,037-11,349,674).
148
C. Belcaro et al. / Gene 565 (2015) 146–149
Autism, learning difficulties, mild intellectual disability Mild intellectual disability, autism, hypotonia, nasal speech
Ataxic cerebral palsy
Male 154 kb, exon 3 out-of-frame (chr5:11432332–11587173)
Male 479 kb, exons 1-3 + 5′UTR, out-of-frame (chr5:11505316–11985200) Maternal (no specific feature) Female 413 kb, exons 2–8 out-of-frame (chr5:11349694–11763030) Paternal (poor attention) Gender Deletion
Male Male NA Female 39 kb, intronic 27,6 kb, exon 14 93 kb, exons 4–9 in frame 113 kb, exons 4–7 (chr5:11,422,171-11,461,920) (chr5:11,322,037-11,349,674) (chr5:11398907–11491980) out-of-frame (chr5:11431816–11545236) De novo De novo Inheritance De novo Maternal (delayed psychomotor development milestones) NA WISC-IV IQ:77 with better Bayley-III IQ: 60 with better IQ WPPSI-III IQ:70, with better language than non-verbal language than non-verbal performance than verbal functions functions functions Autism Short attention span, Delayed developmental Neurological Delayed developmental borderline intellectual milestones, mild intellectual manifestation milestones, mild intellectual disability, memory disability disability impairment
Maternal (low normal intelligence)
Patient 7 (decipher 271234) Patient 6 (decipher 269928) Patient 5 (decipher 248402) Patient 4 (decipher 284528) Patient 3 (Girirajan et al., 2013) Patient 2 Patient 1 Patient
Table 1 Summary of all patients with CTNND2 intragenic deletion.
2.2. Molecular karyotyping Molecular karyotyping analysis was performed on our patients and also on both parents to evaluate CNV parental origin. SNP array analysis, from DNA isolated from peripheral blood lymphocytes, was carried out using the Illumina HumanOmniExpress genotyping microarray, according to the supplier protocol. Data analysis was performed using the Illumina GenomeStudio v.2011.1 software and PennCNV. 3. Results As shown in Fig. 1, patient 1 showed a 39 kb de novo deletion encompassing an intronic sequence of CTNND2 gene (chr5: 11,422,171-11,461,920). His mother presented a duplication of 350 kb in a region near the one involved in the proband (chr5: 10,798,22111,149,808). Nothing has been found in his father. Patient 2 presented a 27,6 kb inherited deletion encompassing exon 14 of CTNND2 gene (chr5: 11,322,037-11,349,674) (Fig. 2). The patient inherited this deletion from his mother. Nothing has been found in his father. 4. Discussion Cri du Chat Syndrome is a well-defined condition in which patients with a large deletion, including CTNND2 gene, have severe mental retardation, while patients with a smaller deletion, not involving CTNND2, are mentally normal or have only a mild intellectual disability (Medina et al., 2000). This aspect confirms the importance of this gene for brain function and development, and it represents an important step in the comprehension of the role of CTNND2 in the nervous system. Very recently, Asdollahi et al. described five patients with intragenic CTNND2 deletion (Table 1). In their review they considered rare exonic CNVs sizing 1–500 kb. The patients previously described presented deletions ranging from 93 kb to 479 kb, therefore larger than those described here. Authors portrayed de novo deletions, inherited deletions from a healthy parent and inherited deletions from a parent with mild intellectual disability (Asadollahi et al., 2014). The phenotypic spectrum is characterized by an autistic spectrum disorder, isolated intellectual disability, and poor attention span. In one case cerebral palsy was present. CTNND2 deletions are not described in normal population databases and this finding supports the idea that CTNND2 deletion has a pathogenic role in some neurodevelopmental disorders with a haploinsufficiency mechanism. Both patients present neurologic involvement that is consistent with the phenotype described in other cases with CTNND2 deletion because of the isolated mild intellectual disability. Patient 1's EEG presented an epileptic pattern in the form of rolandic spikes during sleep without seizures, although this pattern characterizes about 2% of the general pediatric population (Capdevila et al., 2008), being frequently associated with learning disabilities (Cavazzuti et al., 1980). The mothers of the probands both reported having a normal neurological development, although the mother of patient 2, who presented the same deletion, reported delayed walking. Unfortunately, we couldn't perform the array analysis on the sister's DNA because the mother preferred not to investigate further at that time. To better understand the role of the CTNND2 gene in the brain development, we should record that δ-catenin has a crucial role in synaptic functions and plasticity, and this has been demonstrated in mice with targeted disruption of the gene encoding δ-catenin (Kosik et al., 2005). Another evidence of the importance of δ-catenin in the brain's function is the different phenotypes in Cri du Chat Syndrome, whether or not the gene is involved in the deletion. Other researches show that the deletion of CTNND2 is also associated with autism, whereas duplication of this gene is associated with schizophrenia (McMichael et al., 2014). Moreover, CTNND2 has been recently related to other neurological disorders such as Alzheimer's disease, cortical cataract, myopia and
C. Belcaro et al. / Gene 565 (2015) 146–149
also cancer (Nopparat et al., 2015; Jun et al., 2012; Yu et al., 2012). A broad clinical spectrum comes to light from the cases described so far. Probably there are other genetic and environmental factors that contribute to define clinical phenotype. More efforts are needed in order to better understand the δ-catenin role in the pathogenesis of intellectual disability and other neurodevelopmental disorders, but by now the essential involvement of CTNND2 in brain functions is clear. References Alkan, C., Coe, B.P., Eichler, E.E., 2011. Genome structural variation discovery and genotyping. Nat. Rev. Genet. 12 (5), 363–376. Asadollahi, R., et al., 2014. The clinical significance of small copy number variants in neurodevelopmental disorders. J. Med. Genet. 51 (10), 677–688. Capdevila, O.S., et al., 2008. Prevalence of epileptiform activity in healthy children during sleep. Sleep Med. 9 (3), 303–309. Cavazzuti, G.B., Cappella, L., Nalin, A., 1980. Longitudinal study of epileptiform EEG patterns in normal children. Epilepsia 21 (1), 43–55. Gandin, I., et al., 2014. Excess of runs of homozygosity is associated with severe cognitive impairment in intellectual disability. Genet. Med. Girirajan, S., Dennis, M.Y., Baker, C., Malig, M., Coe, B.P., Campbell, C.D., et al., 2013. Refinement and discovery of new hotspots of copy-number variationassociated with autism spectrum disorder. Am. J. Hum. Genet. 92, 221–237.
149
Hochstenbach, R., et al., 2011. Genome arrays for the detection of copy number variations in idiopathic mental retardation, idiopathic generalized epilepsy and neuropsychiatric disorders: lessons for diagnostic workflow and research. Cytogenet. Genome Res. 135 (3–4), 174–202. http://omim.org/entry/604275; OMIM Database. Jun, G., et al., 2012. delta-Catenin is genetically and biologically associated with cortical cataract and future Alzheimer-related structural and functional brain changes. PLoS One 7 (9), e43728. Kosik, K.S., et al., 2005. Delta-catenin at the synaptic-adherens junction. Trends Cell Biol. 15 (3), 172–178. Lee, J.A., Lupski, J.R., 2006. Genomic rearrangements and gene copy-number alterations as a cause of nervous system disorders. Neuron 52 (1), 103–121. McMichael, G., et al., 2014. Rare copy number variation in cerebral palsy. Eur. J. Hum. Genet. 22 (1), 40–45. Medina, M., et al., 2000. Hemizygosity of delta-catenin (CTNND2) is associated with severe mental retardation in cri-du-chat syndrome. Genomics 63 (2), 157–164. Nopparat, J., et al., 2015. delta-Catenin, a Wnt/beta-catenin modulator, reveals inducible mutagenesis promoting cancer cell survival adaptation and metabolic reprogramming. Oncogene 34 (12), 1542–1552. Yu, Z., et al., 2012. Polymorphisms in the CTNND2 gene and 11q24.1 genomic region are associated with pathological myopia in a Chinese population. Ophthalmologica 228 (2), 123–129.