Identification of a microdeletion at the 7q33‐q35 disrupting the <i>CNTNAP2</i> gene in a Brazilian stuttering case

Petrin, Aline; Giacheti, Célia Maria; Maximino, Luciana Paula; Abramides, Dagma Venturini Marques; Zanchetta, Sthella; Rossi, Natalia Freitas; Richieri-Costa, Antônio; Murray, Jeffrey C.

doi:10.1002/ajmg.a.33749

Cited by 58 publications

(44 citation statements)

References 40 publications

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“…In a patient with GTS a disruption distal to exon 6 of CNTNAP2 was found [Verkerk et al, 2003]. This patient and the cases reported by Poot et al [2010b], Petrin et al [2010], and an unpublished case of Jenkins and Tezcan (personal communication) all share some form of language impairment [for reviews see Roll et al, 2010]. Comparisons of structural variations in the CNTNAP2 gene (DE-CIPHER #250286, Petrin et al, [2010] Poot et al, [2010b and Jenkins and Tezcan patients in fig.…”

Section: Interaction Of Cnvs With Other Loci and Genesmentioning

confidence: 99%

“…This patient and the cases reported by Poot et al [2010b], Petrin et al [2010], and an unpublished case of Jenkins and Tezcan (personal communication) all share some form of language impairment [for reviews see Roll et al, 2010]. Comparisons of structural variations in the CNTNAP2 gene (DE-CIPHER #250286, Petrin et al, [2010] Poot et al, [2010b and Jenkins and Tezcan patients in fig. 2 ) allow mapping of a language impairment locus to the FOXP2 binding sites within intron 1 of CNTNAP2 [Vernes et al, 2008].…”

Section: Interaction Of Cnvs With Other Loci and Genesmentioning

confidence: 99%

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Disentangling the Myriad Genomics of Complex Disorders, Specifically Focusing on Autism, Epilepsy, and Schizophrenia

Poot

Smagt

Brilstra

et al. 2011

Cytogenet Genome Res

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Analyses of structural genome variation by array-CGH have dramatically enhanced our ability to detect copy number variations (CNVs). De novo CNVs and those co-segregating with disease in a family are generally interpreted as pathogenic. Yet, often CNVs, such as recurrent microdeletions in region 15q13.3, are not so clearly pathogenic. Here we discuss potential confounding mechanisms that may lead to the phenotypic pleiotropy of CNVs, such as unmasking of recessive alleles by hemizygous deletions, interaction of CNVs with other loci and genes, genetic epistasis, allelic exclusion, and somatic mosaicism. We illustrate some of these mechanisms with a detailed analysis of recent studies of CNVs involving MCPH1, AUTS2, CNTNAP2, and mutations in GRIN2B. Next we discuss the clinical ramifications of these findings and urge workers to avoid ‘diagnostic fatalism’ (i.e., halting all genetic investigation after the detection of a single CNV) and address some of the future challenges likely to result from implementations of next generation sequencing techniques.

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Section: Interaction Of Cnvs With Other Loci and Genesmentioning

confidence: 99%

Section: Interaction Of Cnvs With Other Loci and Genesmentioning

confidence: 99%

Disentangling the Myriad Genomics of Complex Disorders, Specifically Focusing on Autism, Epilepsy, and Schizophrenia

Poot

Smagt

Brilstra

et al. 2011

Cytogenet Genome Res

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“…4). In addition, mutations in CNTNAP2 also have been linked to epilepsy (5-7), Tourette syndrome (8,9), schizophrenia (5,7,10), attention deficit hyperactivity disorder (ADHD) (11), learning disability (12,13), and language impairment (14)(15)(16). Thus, CNTNAP2 is of central importance for human brain function, as additionally shown by recent in vivo MRI studies in which variations in the CNTNAP2 gene were associated with reduced frontal gray matter and altered functional connectivity (17,18).…”

mentioning

confidence: 96%

Candidate autism gene screen identifies critical role for cell-adhesion molecule CASPR2 in dendritic arborization and spine development

Anderson

Galfin

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

206

179

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Mutations in the contactin-associated protein 2 (CNTNAP2) gene encoding CASPR2, a neurexin-related cell-adhesion molecule, predispose to autism, but the function of CASPR2 in neural circuit assembly remains largely unknown. In a knockdown survey of autism candidate genes, we found that CASPR2 is required for normal development of neural networks. RNAi-mediated knockdown of CASPR2 produced a cell-autonomous decrease in dendritic arborization and spine development in pyramidal neurons, leading to a global decline in excitatory and inhibitory synapse numbers and a decrease in synaptic transmission without a detectable change in the properties of these synapses. Our data suggest that in addition to the previously described role of CASPR2 in mature neurons, where CASPR2 organizes nodal microdomains of myelinated axons, CASPR2 performs an earlier organizational function in developing neurons that is essential for neural circuit assembly and operates coincident with the time of autism spectrum disorder (ASD) pathogenesis.dendrite | synaptogenesis A utism spectrum disorders (ASDs) comprise a heterogeneous group of early developmental diseases characterized by repetitive and stereotypic behaviors and impairments in social interactions and language development. ASDs are highly heritable, with recent studies linking mutations at hundreds of genes to ASDs (1-3). These findings raised the fundamental question of how these genes might act in neural circuits without being essential for all brain function. Here, we have attempted to address this question by using a Ca 2+ -imaging screening platform to visualize changes in excitatory network activity following shRNA-mediated knockdown (KD) of prominent cell-adhesion molecules that have been repeatedly implicated in the development of ASDs. We found that molecular manipulation of several ASD candidate genes profoundly influences network activity as monitored by this assay. We observed the biggest effects with the neuronal cell-adhesion molecule contactin-associated protein 2 (CASPR2) that is encoded by the CNTNAP2 gene, leading us to specifically focus on the mechanisms by which this cell-adhesion molecule influences neural circuit development.Mutations in the CNTNAP2 gene have been repeatedly identified in ASD patients (for review, see ref. 4). In addition, mutations in CNTNAP2 also have been linked to epilepsy (5-7), Tourette syndrome (8, 9), schizophrenia (5, 7, 10), attention deficit hyperactivity disorder (ADHD) (11), learning disability (12, 13), and language impairment (14-16). Thus, CNTNAP2 is of central importance for human brain function, as additionally shown by recent in vivo MRI studies in which variations in the CNTNAP2 gene were associated with reduced frontal gray matter and altered functional connectivity (17,18).CASPR2 is a member of the contactin-associated protein family (19). CASPRs are referred to as neurexin IV in Drosophila and are highly homologous to neurexins, which are presynaptic celladhesion molecules (20-23). CASPR2 is best known for its role in mye...

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“…A likely explanation for the observed autism would be haploinsufficiency for this part of CNTNAP2 [Poot et al, 2011]. This is not necessarily the only mechanism for the observed autism in these patients, since a patient described by Petrin et al [2010], exhibiting stuttering, was not autistic. A second region, ranging from exon 2 to the 3 ′ terminus of the gene, may contain 2 sites that predispose to risk for seizures [Zweier et al, 2007;Friedman et al, 2008;Mefford et al, 2010].…”

Section: Gene Haploinsufficiencymentioning

confidence: 99%

“…By CNV mapping, several investigators found de novo heterozygous losses of the proximal part of CNTNAP2 in patients with autism [Alarcon et al, 2008], Pitt-Hopkins syndrome [Zweier et al, 2007], ADHD [Elia et al, 2010], stuttering [Petrin et al, 2010], and ID [Mikhail et al, 2011] ( fig. 2 , red bars) .…”

Section: Protein-protein Interactions Involving Caspr2mentioning

confidence: 99%

Connecting the CNTNAP2 Networks with Neurodevelopmental Disorders

Poot¹

2015

Mol Syndromol

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Based on genomic rearrangements and copy number variations, the contactin-associated protein-like 2 gene (CNTNAP2) has been implicated in neurodevelopmental disorders such as Gilles de la Tourette syndrome, intellectual disability, obsessive compulsive disorder, cortical dysplasia-focal epilepsy syndrome, autism, schizophrenia, Pitt-Hopkins syndrome, and attention deficit hyperactivity disorder. To explain the phenotypic pleiotropy of CNTNAP2 alterations, several hypotheses have been put forward. Those include gene disruption, loss of a gene copy by a heterozygous deletion, altered regulation of gene expression due to loss of transcription factor binding and DNA methylation sites, and mutations in the amino acid sequence of the encoded protein which may provoke altered interactions of the CNTNAP2-encoded protein, Caspr2, with other proteins. Also exome sequencing, which covers <0.2% of the CNTNAP2 genomic DNA, has revealed numerous single nucleotide variants in healthy individuals and in patients with neurodevelopmental disorders. In some of these disorders, disruption of CNTNAP2 may be interpreted as a susceptibility factor rather than a directly causative mutation. In addition to being associated with impaired development of language, CNTNAP2 may turn out to be a central node in the molecular networks controlling neurodevelopment. This review discusses the impact of CNTNAP2 mutations on its functioning at multiple levels of the combinatorial genetic networks that govern brain development. In addition, recommendations for genomic testing in the context of clinical genetic management of patients with neurodevelopmental disorders and their families are put forward.

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Identification of a microdeletion at the 7q33‐q35 disrupting the CNTNAP2 gene in a Brazilian stuttering case

Cited by 58 publications

References 40 publications

Disentangling the Myriad Genomics of Complex Disorders, Specifically Focusing on Autism, Epilepsy, and Schizophrenia

Disentangling the Myriad Genomics of Complex Disorders, Specifically Focusing on Autism, Epilepsy, and Schizophrenia

Candidate autism gene screen identifies critical role for cell-adhesion molecule CASPR2 in dendritic arborization and spine development

Connecting the CNTNAP2 Networks with Neurodevelopmental Disorders

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