Neurodevelopmental disorders associated with dosage imbalance of ZBTB20 correlate with the morbidity spectrum of ZBTB20 candidate target genes

Malene B Rasmussen; Jakob V Nielsen; Charles M Lourenço; Joana B  Melo; Christina Halgren; Camila V L Geraldi; Wilson Marques; Guilherme R Rodrigues; Mads Thomassen; Mads Bak; Claus Hansen; Susana I Ferreira; Margarida Venâncio; Karen F Henriksen; Allan Lind-Thomsen; Isabel M Carreira; Niels A Jensen; Niels Tommerup

doi:10.1136/jmedgenet-2014-102535

Neurodevelopmental disorders associated with dosage imbalance of ZBTB20 correlate with the morbidity spectrum of ZBTB20 candidate target genes

Malene B Rasmussen, Jakob V Nielsen, Charles M Lourenço, Joana B Melo, Christina Halgren, Camila V L Geraldi, Wilson Marques, Guilherme R Rodrigues, Mads Thomassen, Mads Bak, Claus Hansen, Susana I Ferreira, Margarida Venâncio, Karen F Henriksen, Allan Lind-Thomsen, Isabel M Carreira, Niels A Jensen, Niels Tommerup

Medical Genetics Program

23 Citations (Scopus)

Abstract

BACKGROUND: Recently, a number of patients have been described with structural rearrangements at 3q13.31, delineating a novel microdeletion syndrome with common clinical features including developmental delay and other neurodevelopmental disorders (NDD). A smallest region of overlapping deletions (SRO) involved five RefSeq genes, including the transcription factor gene ZBTB20 and the dopamine receptor gene DRD3, considered as candidate genes for the syndrome.

METHODS AND RESULTS: We used array comparative genomic hybridization and next-generation mate-pair sequencing to identify key structural rearrangements involving ZBTB20 in two patients with NDD. In a patient with developmental delay, attention-deficit hyperactivity disorder, psychosis, Tourette's syndrome and autistic traits, a de novo balanced t(3;18) translocation truncated ZBTB20. The other breakpoint did not disrupt any gene. In a second patient with developmental delay and autism, we detected the first microdeletion at 3q13.31, which truncated ZBTB20 but did not involve DRD3 or the other genes within the previously defined SRO. Zbtb20 directly represses 346 genes in the developing murine brain. Of the 342 human orthologous ZBTB20 candidate target genes, we found 68 associated with NDD. Using chromatin immunoprecipitation and quantitative PCR, we validated the in vivo binding of Zbtb20 in evolutionary conserved regions in six of these genes (Cntn4, Gad1, Nrxn1, Nrxn3, Scn2a, Snap25).

CONCLUSIONS: Our study links dosage imbalance of ZBTB20 to a range of neurodevelopmental, cognitive and psychiatric disorders, likely mediated by dysregulation of multiple ZBTB20 target genes, and provides new knowledge on the genetic background of the NDD seen in the 3q13.31 microdeletion syndrome.

Original language	English
Journal	Journal of Medical Genetics
Volume	51
Issue number	9
Pages (from-to)	605-613
Number of pages	9
ISSN	0022-2593
DOIs	https://doi.org/10.1136/jmedgenet-2014-102535
Publication status	Published - Sept 2014

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Rasmussen, M. B., Nielsen, J. V., Lourenço, C. M., Melo, J. B., Halgren, C., Geraldi, C. V. L., Marques, W., Rodrigues, G. R., Thomassen, M., Bak, M., Hansen, C., Ferreira, S. I., Venâncio, M., Henriksen, K. F., Lind-Thomsen, A., Carreira, I. M., Jensen, N. A., & Tommerup, N. (2014). Neurodevelopmental disorders associated with dosage imbalance of ZBTB20 correlate with the morbidity spectrum of ZBTB20 candidate target genes. Journal of Medical Genetics, 51(9), 605-613. https://doi.org/10.1136/jmedgenet-2014-102535

Neurodevelopmental disorders associated with dosage imbalance of ZBTB20 correlate with the morbidity spectrum of ZBTB20 candidate target genes. / Rasmussen, Malene B; Nielsen, Jakob V; Lourenço, Charles M et al.

In: Journal of Medical Genetics, Vol. 51, No. 9, 09.2014, p. 605-613.

Research output: Contribution to journal › Journal article › Research › peer-review

Rasmussen, MB, Nielsen, JV, Lourenço, CM, Melo, JB, Halgren, C, Geraldi, CVL, Marques, W, Rodrigues, GR, Thomassen, M, Bak, M, Hansen, C, Ferreira, SI, Venâncio, M, Henriksen, KF, Lind-Thomsen, A, Carreira, IM, Jensen, NA & Tommerup, N 2014, 'Neurodevelopmental disorders associated with dosage imbalance of ZBTB20 correlate with the morbidity spectrum of ZBTB20 candidate target genes', Journal of Medical Genetics, vol. 51, no. 9, pp. 605-613. https://doi.org/10.1136/jmedgenet-2014-102535

@article{3bbb02c1734d4245a899ae281a2b0b08,

title = "Neurodevelopmental disorders associated with dosage imbalance of ZBTB20 correlate with the morbidity spectrum of ZBTB20 candidate target genes",

abstract = "BACKGROUND: Recently, a number of patients have been described with structural rearrangements at 3q13.31, delineating a novel microdeletion syndrome with common clinical features including developmental delay and other neurodevelopmental disorders (NDD). A smallest region of overlapping deletions (SRO) involved five RefSeq genes, including the transcription factor gene ZBTB20 and the dopamine receptor gene DRD3, considered as candidate genes for the syndrome.METHODS AND RESULTS: We used array comparative genomic hybridization and next-generation mate-pair sequencing to identify key structural rearrangements involving ZBTB20 in two patients with NDD. In a patient with developmental delay, attention-deficit hyperactivity disorder, psychosis, Tourette's syndrome and autistic traits, a de novo balanced t(3;18) translocation truncated ZBTB20. The other breakpoint did not disrupt any gene. In a second patient with developmental delay and autism, we detected the first microdeletion at 3q13.31, which truncated ZBTB20 but did not involve DRD3 or the other genes within the previously defined SRO. Zbtb20 directly represses 346 genes in the developing murine brain. Of the 342 human orthologous ZBTB20 candidate target genes, we found 68 associated with NDD. Using chromatin immunoprecipitation and quantitative PCR, we validated the in vivo binding of Zbtb20 in evolutionary conserved regions in six of these genes (Cntn4, Gad1, Nrxn1, Nrxn3, Scn2a, Snap25).CONCLUSIONS: Our study links dosage imbalance of ZBTB20 to a range of neurodevelopmental, cognitive and psychiatric disorders, likely mediated by dysregulation of multiple ZBTB20 target genes, and provides new knowledge on the genetic background of the NDD seen in the 3q13.31 microdeletion syndrome.",

author = "Rasmussen, {Malene B} and Nielsen, {Jakob V} and Louren{\c c}o, {Charles M} and Melo, {Joana B} and Christina Halgren and Geraldi, {Camila V L} and Wilson Marques and Rodrigues, {Guilherme R} and Mads Thomassen and Mads Bak and Claus Hansen and Ferreira, {Susana I} and Margarida Ven{\^a}ncio and Henriksen, {Karen F} and Allan Lind-Thomsen and Carreira, {Isabel M} and Jensen, {Niels A} and Niels Tommerup",

note = "Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.",

year = "2014",

month = sep,

doi = "10.1136/jmedgenet-2014-102535",

language = "English",

volume = "51",

pages = "605--613",

journal = "Journal of Medical Genetics",

issn = "0022-2593",

publisher = "B M J Group",

number = "9",

}

TY - JOUR

T1 - Neurodevelopmental disorders associated with dosage imbalance of ZBTB20 correlate with the morbidity spectrum of ZBTB20 candidate target genes

AU - Rasmussen, Malene B

AU - Nielsen, Jakob V

AU - Lourenço, Charles M

AU - Melo, Joana B

AU - Halgren, Christina

AU - Geraldi, Camila V L

AU - Marques, Wilson

AU - Rodrigues, Guilherme R

AU - Thomassen, Mads

AU - Bak, Mads

AU - Hansen, Claus

AU - Ferreira, Susana I

AU - Venâncio, Margarida

AU - Henriksen, Karen F

AU - Lind-Thomsen, Allan

AU - Carreira, Isabel M

AU - Jensen, Niels A

AU - Tommerup, Niels

N1 - Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

PY - 2014/9

Y1 - 2014/9

N2 - BACKGROUND: Recently, a number of patients have been described with structural rearrangements at 3q13.31, delineating a novel microdeletion syndrome with common clinical features including developmental delay and other neurodevelopmental disorders (NDD). A smallest region of overlapping deletions (SRO) involved five RefSeq genes, including the transcription factor gene ZBTB20 and the dopamine receptor gene DRD3, considered as candidate genes for the syndrome.METHODS AND RESULTS: We used array comparative genomic hybridization and next-generation mate-pair sequencing to identify key structural rearrangements involving ZBTB20 in two patients with NDD. In a patient with developmental delay, attention-deficit hyperactivity disorder, psychosis, Tourette's syndrome and autistic traits, a de novo balanced t(3;18) translocation truncated ZBTB20. The other breakpoint did not disrupt any gene. In a second patient with developmental delay and autism, we detected the first microdeletion at 3q13.31, which truncated ZBTB20 but did not involve DRD3 or the other genes within the previously defined SRO. Zbtb20 directly represses 346 genes in the developing murine brain. Of the 342 human orthologous ZBTB20 candidate target genes, we found 68 associated with NDD. Using chromatin immunoprecipitation and quantitative PCR, we validated the in vivo binding of Zbtb20 in evolutionary conserved regions in six of these genes (Cntn4, Gad1, Nrxn1, Nrxn3, Scn2a, Snap25).CONCLUSIONS: Our study links dosage imbalance of ZBTB20 to a range of neurodevelopmental, cognitive and psychiatric disorders, likely mediated by dysregulation of multiple ZBTB20 target genes, and provides new knowledge on the genetic background of the NDD seen in the 3q13.31 microdeletion syndrome.

AB - BACKGROUND: Recently, a number of patients have been described with structural rearrangements at 3q13.31, delineating a novel microdeletion syndrome with common clinical features including developmental delay and other neurodevelopmental disorders (NDD). A smallest region of overlapping deletions (SRO) involved five RefSeq genes, including the transcription factor gene ZBTB20 and the dopamine receptor gene DRD3, considered as candidate genes for the syndrome.METHODS AND RESULTS: We used array comparative genomic hybridization and next-generation mate-pair sequencing to identify key structural rearrangements involving ZBTB20 in two patients with NDD. In a patient with developmental delay, attention-deficit hyperactivity disorder, psychosis, Tourette's syndrome and autistic traits, a de novo balanced t(3;18) translocation truncated ZBTB20. The other breakpoint did not disrupt any gene. In a second patient with developmental delay and autism, we detected the first microdeletion at 3q13.31, which truncated ZBTB20 but did not involve DRD3 or the other genes within the previously defined SRO. Zbtb20 directly represses 346 genes in the developing murine brain. Of the 342 human orthologous ZBTB20 candidate target genes, we found 68 associated with NDD. Using chromatin immunoprecipitation and quantitative PCR, we validated the in vivo binding of Zbtb20 in evolutionary conserved regions in six of these genes (Cntn4, Gad1, Nrxn1, Nrxn3, Scn2a, Snap25).CONCLUSIONS: Our study links dosage imbalance of ZBTB20 to a range of neurodevelopmental, cognitive and psychiatric disorders, likely mediated by dysregulation of multiple ZBTB20 target genes, and provides new knowledge on the genetic background of the NDD seen in the 3q13.31 microdeletion syndrome.

U2 - 10.1136/jmedgenet-2014-102535

DO - 10.1136/jmedgenet-2014-102535

M3 - Journal article

C2 - 25062845

SN - 0022-2593

VL - 51

SP - 605

EP - 613

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

IS - 9

ER -

Neurodevelopmental disorders associated with dosage imbalance of ZBTB20 correlate with the morbidity spectrum of ZBTB20 candidate target genes

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