Genetic analysis of Wnt/PCP genes in neural tube defects

Background Mouse homozygous mutants in Wnt/planar cell polarity (PCP) pathway genes have been shown to cause neural tube defects (NTDs) through the disruption of normal morphogenetic processes critical to neural tube closure (NTC). Knockout mice that are heterozygotes of single PCP genes likely fail...
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Autor*in:	Chen, Zhongzhong [verfasserIn] Lei, Yunping Cao, Xuanye Zheng, Yufang Wang, Fang Bao, Yihua Peng, Rui Finnell, Richard H. Zhang, Ting Wang, Hongyan

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2018

Schlagwörter:	Neural tube defects PCP (planar cell polarity) Wnt Variant CELSR

Anmerkung:	© The Author(s). 2018

Übergeordnetes Werk:	Enthalten in: BMC medical genomics - London : BioMed Central, 2008, 11(2018), 1 vom: 04. Apr.
Übergeordnetes Werk:	volume:11 ; year:2018 ; number:1 ; day:04 ; month:04

Links:	Volltext

DOI / URN:	10.1186/s12920-018-0355-9

Katalog-ID:	SPR028473566

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520			\|a Background Mouse homozygous mutants in Wnt/planar cell polarity (PCP) pathway genes have been shown to cause neural tube defects (NTDs) through the disruption of normal morphogenetic processes critical to neural tube closure (NTC). Knockout mice that are heterozygotes of single PCP genes likely fail to produce NTD phenotypes, yet damaging variants detected in human NTDs are almost always heterozygous, suggesting that other deleterious interacting variants are likely to be present. Nonetheless, the Wnt/PCP pathway remains a genetic hotspot. Addressing these issues is essential for understanding the genetic etiology of human NTDs. Methods We performed targeted next-generation sequencing (NGS) on 30 NTD-predisposing Wnt/PCP pathway genes in 184 Chinese NTD cases. We subsequently replicated our findings for the CELSR1 gene in an independent cohort of 292 Caucasian NTD samples from the USA. Functional validations were confirmed using in vitro assays. Results CELSR1, CELSR2 and CELSR3 genes were significantly clustered with rare driver coding mutations (q-value< 0.05) demonstrated by OncodriveCLUST. During the validation stage, the number of rare loss of function (LoF) variants in CELSR1 was significantly enriched in NTDs compared with the LoF counts in the ExAC database (p < 0.001). Functional studies indicated compound heterozygote variants of CELSR2 p.Thr2026Met and DVL3 p.Asp403Asn result in down regulation of PCP signals. Conclusions These data indicate rare damaging variants of the CELSR genes, identified in ~ 14% of NTD cases, are expected to be driver genes in the Wnt/PCP pathway. Compound damaging variants of CELSR genes and other Wnt/PCP genes, which were observed in 3.3% of the studied NTD cohort, are also expected to amplify these effects at the pathway level.
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allfields	10.1186/s12920-018-0355-9 doi (DE-627)SPR028473566 (SPR)s12920-018-0355-9-e DE-627 ger DE-627 rakwb eng Chen, Zhongzhong verfasserin aut Genetic analysis of Wnt/PCP genes in neural tube defects 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2018 Background Mouse homozygous mutants in Wnt/planar cell polarity (PCP) pathway genes have been shown to cause neural tube defects (NTDs) through the disruption of normal morphogenetic processes critical to neural tube closure (NTC). Knockout mice that are heterozygotes of single PCP genes likely fail to produce NTD phenotypes, yet damaging variants detected in human NTDs are almost always heterozygous, suggesting that other deleterious interacting variants are likely to be present. Nonetheless, the Wnt/PCP pathway remains a genetic hotspot. Addressing these issues is essential for understanding the genetic etiology of human NTDs. Methods We performed targeted next-generation sequencing (NGS) on 30 NTD-predisposing Wnt/PCP pathway genes in 184 Chinese NTD cases. We subsequently replicated our findings for the CELSR1 gene in an independent cohort of 292 Caucasian NTD samples from the USA. Functional validations were confirmed using in vitro assays. Results CELSR1, CELSR2 and CELSR3 genes were significantly clustered with rare driver coding mutations (q-value< 0.05) demonstrated by OncodriveCLUST. During the validation stage, the number of rare loss of function (LoF) variants in CELSR1 was significantly enriched in NTDs compared with the LoF counts in the ExAC database (p < 0.001). Functional studies indicated compound heterozygote variants of CELSR2 p.Thr2026Met and DVL3 p.Asp403Asn result in down regulation of PCP signals. Conclusions These data indicate rare damaging variants of the CELSR genes, identified in ~ 14% of NTD cases, are expected to be driver genes in the Wnt/PCP pathway. Compound damaging variants of CELSR genes and other Wnt/PCP genes, which were observed in 3.3% of the studied NTD cohort, are also expected to amplify these effects at the pathway level. Neural tube defects (dpeaa)DE-He213 PCP (planar cell polarity) (dpeaa)DE-He213 Wnt (dpeaa)DE-He213 Variant (dpeaa)DE-He213 CELSR (dpeaa)DE-He213 Lei, Yunping aut Cao, Xuanye aut Zheng, Yufang aut Wang, Fang aut Bao, Yihua aut Peng, Rui aut Finnell, Richard H. aut Zhang, Ting aut Wang, Hongyan (orcid)0000-0001-6662-5837 aut Enthalten in BMC medical genomics London : BioMed Central, 2008 11(2018), 1 vom: 04. Apr. (DE-627)559080824 (DE-600)2411865-5 1755-8794 nnns volume:11 year:2018 number:1 day:04 month:04 https://dx.doi.org/10.1186/s12920-018-0355-9 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2018 1 04 04
spelling	10.1186/s12920-018-0355-9 doi (DE-627)SPR028473566 (SPR)s12920-018-0355-9-e DE-627 ger DE-627 rakwb eng Chen, Zhongzhong verfasserin aut Genetic analysis of Wnt/PCP genes in neural tube defects 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2018 Background Mouse homozygous mutants in Wnt/planar cell polarity (PCP) pathway genes have been shown to cause neural tube defects (NTDs) through the disruption of normal morphogenetic processes critical to neural tube closure (NTC). Knockout mice that are heterozygotes of single PCP genes likely fail to produce NTD phenotypes, yet damaging variants detected in human NTDs are almost always heterozygous, suggesting that other deleterious interacting variants are likely to be present. Nonetheless, the Wnt/PCP pathway remains a genetic hotspot. Addressing these issues is essential for understanding the genetic etiology of human NTDs. Methods We performed targeted next-generation sequencing (NGS) on 30 NTD-predisposing Wnt/PCP pathway genes in 184 Chinese NTD cases. We subsequently replicated our findings for the CELSR1 gene in an independent cohort of 292 Caucasian NTD samples from the USA. Functional validations were confirmed using in vitro assays. Results CELSR1, CELSR2 and CELSR3 genes were significantly clustered with rare driver coding mutations (q-value< 0.05) demonstrated by OncodriveCLUST. During the validation stage, the number of rare loss of function (LoF) variants in CELSR1 was significantly enriched in NTDs compared with the LoF counts in the ExAC database (p < 0.001). Functional studies indicated compound heterozygote variants of CELSR2 p.Thr2026Met and DVL3 p.Asp403Asn result in down regulation of PCP signals. Conclusions These data indicate rare damaging variants of the CELSR genes, identified in ~ 14% of NTD cases, are expected to be driver genes in the Wnt/PCP pathway. Compound damaging variants of CELSR genes and other Wnt/PCP genes, which were observed in 3.3% of the studied NTD cohort, are also expected to amplify these effects at the pathway level. Neural tube defects (dpeaa)DE-He213 PCP (planar cell polarity) (dpeaa)DE-He213 Wnt (dpeaa)DE-He213 Variant (dpeaa)DE-He213 CELSR (dpeaa)DE-He213 Lei, Yunping aut Cao, Xuanye aut Zheng, Yufang aut Wang, Fang aut Bao, Yihua aut Peng, Rui aut Finnell, Richard H. aut Zhang, Ting aut Wang, Hongyan (orcid)0000-0001-6662-5837 aut Enthalten in BMC medical genomics London : BioMed Central, 2008 11(2018), 1 vom: 04. Apr. (DE-627)559080824 (DE-600)2411865-5 1755-8794 nnns volume:11 year:2018 number:1 day:04 month:04 https://dx.doi.org/10.1186/s12920-018-0355-9 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2018 1 04 04
allfields_unstemmed	10.1186/s12920-018-0355-9 doi (DE-627)SPR028473566 (SPR)s12920-018-0355-9-e DE-627 ger DE-627 rakwb eng Chen, Zhongzhong verfasserin aut Genetic analysis of Wnt/PCP genes in neural tube defects 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2018 Background Mouse homozygous mutants in Wnt/planar cell polarity (PCP) pathway genes have been shown to cause neural tube defects (NTDs) through the disruption of normal morphogenetic processes critical to neural tube closure (NTC). Knockout mice that are heterozygotes of single PCP genes likely fail to produce NTD phenotypes, yet damaging variants detected in human NTDs are almost always heterozygous, suggesting that other deleterious interacting variants are likely to be present. Nonetheless, the Wnt/PCP pathway remains a genetic hotspot. Addressing these issues is essential for understanding the genetic etiology of human NTDs. Methods We performed targeted next-generation sequencing (NGS) on 30 NTD-predisposing Wnt/PCP pathway genes in 184 Chinese NTD cases. We subsequently replicated our findings for the CELSR1 gene in an independent cohort of 292 Caucasian NTD samples from the USA. Functional validations were confirmed using in vitro assays. Results CELSR1, CELSR2 and CELSR3 genes were significantly clustered with rare driver coding mutations (q-value< 0.05) demonstrated by OncodriveCLUST. During the validation stage, the number of rare loss of function (LoF) variants in CELSR1 was significantly enriched in NTDs compared with the LoF counts in the ExAC database (p < 0.001). Functional studies indicated compound heterozygote variants of CELSR2 p.Thr2026Met and DVL3 p.Asp403Asn result in down regulation of PCP signals. Conclusions These data indicate rare damaging variants of the CELSR genes, identified in ~ 14% of NTD cases, are expected to be driver genes in the Wnt/PCP pathway. Compound damaging variants of CELSR genes and other Wnt/PCP genes, which were observed in 3.3% of the studied NTD cohort, are also expected to amplify these effects at the pathway level. Neural tube defects (dpeaa)DE-He213 PCP (planar cell polarity) (dpeaa)DE-He213 Wnt (dpeaa)DE-He213 Variant (dpeaa)DE-He213 CELSR (dpeaa)DE-He213 Lei, Yunping aut Cao, Xuanye aut Zheng, Yufang aut Wang, Fang aut Bao, Yihua aut Peng, Rui aut Finnell, Richard H. aut Zhang, Ting aut Wang, Hongyan (orcid)0000-0001-6662-5837 aut Enthalten in BMC medical genomics London : BioMed Central, 2008 11(2018), 1 vom: 04. Apr. (DE-627)559080824 (DE-600)2411865-5 1755-8794 nnns volume:11 year:2018 number:1 day:04 month:04 https://dx.doi.org/10.1186/s12920-018-0355-9 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2018 1 04 04
allfieldsGer	10.1186/s12920-018-0355-9 doi (DE-627)SPR028473566 (SPR)s12920-018-0355-9-e DE-627 ger DE-627 rakwb eng Chen, Zhongzhong verfasserin aut Genetic analysis of Wnt/PCP genes in neural tube defects 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2018 Background Mouse homozygous mutants in Wnt/planar cell polarity (PCP) pathway genes have been shown to cause neural tube defects (NTDs) through the disruption of normal morphogenetic processes critical to neural tube closure (NTC). Knockout mice that are heterozygotes of single PCP genes likely fail to produce NTD phenotypes, yet damaging variants detected in human NTDs are almost always heterozygous, suggesting that other deleterious interacting variants are likely to be present. Nonetheless, the Wnt/PCP pathway remains a genetic hotspot. Addressing these issues is essential for understanding the genetic etiology of human NTDs. Methods We performed targeted next-generation sequencing (NGS) on 30 NTD-predisposing Wnt/PCP pathway genes in 184 Chinese NTD cases. We subsequently replicated our findings for the CELSR1 gene in an independent cohort of 292 Caucasian NTD samples from the USA. Functional validations were confirmed using in vitro assays. Results CELSR1, CELSR2 and CELSR3 genes were significantly clustered with rare driver coding mutations (q-value< 0.05) demonstrated by OncodriveCLUST. During the validation stage, the number of rare loss of function (LoF) variants in CELSR1 was significantly enriched in NTDs compared with the LoF counts in the ExAC database (p < 0.001). Functional studies indicated compound heterozygote variants of CELSR2 p.Thr2026Met and DVL3 p.Asp403Asn result in down regulation of PCP signals. Conclusions These data indicate rare damaging variants of the CELSR genes, identified in ~ 14% of NTD cases, are expected to be driver genes in the Wnt/PCP pathway. Compound damaging variants of CELSR genes and other Wnt/PCP genes, which were observed in 3.3% of the studied NTD cohort, are also expected to amplify these effects at the pathway level. Neural tube defects (dpeaa)DE-He213 PCP (planar cell polarity) (dpeaa)DE-He213 Wnt (dpeaa)DE-He213 Variant (dpeaa)DE-He213 CELSR (dpeaa)DE-He213 Lei, Yunping aut Cao, Xuanye aut Zheng, Yufang aut Wang, Fang aut Bao, Yihua aut Peng, Rui aut Finnell, Richard H. aut Zhang, Ting aut Wang, Hongyan (orcid)0000-0001-6662-5837 aut Enthalten in BMC medical genomics London : BioMed Central, 2008 11(2018), 1 vom: 04. Apr. (DE-627)559080824 (DE-600)2411865-5 1755-8794 nnns volume:11 year:2018 number:1 day:04 month:04 https://dx.doi.org/10.1186/s12920-018-0355-9 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2018 1 04 04
allfieldsSound	10.1186/s12920-018-0355-9 doi (DE-627)SPR028473566 (SPR)s12920-018-0355-9-e DE-627 ger DE-627 rakwb eng Chen, Zhongzhong verfasserin aut Genetic analysis of Wnt/PCP genes in neural tube defects 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2018 Background Mouse homozygous mutants in Wnt/planar cell polarity (PCP) pathway genes have been shown to cause neural tube defects (NTDs) through the disruption of normal morphogenetic processes critical to neural tube closure (NTC). Knockout mice that are heterozygotes of single PCP genes likely fail to produce NTD phenotypes, yet damaging variants detected in human NTDs are almost always heterozygous, suggesting that other deleterious interacting variants are likely to be present. Nonetheless, the Wnt/PCP pathway remains a genetic hotspot. Addressing these issues is essential for understanding the genetic etiology of human NTDs. Methods We performed targeted next-generation sequencing (NGS) on 30 NTD-predisposing Wnt/PCP pathway genes in 184 Chinese NTD cases. We subsequently replicated our findings for the CELSR1 gene in an independent cohort of 292 Caucasian NTD samples from the USA. Functional validations were confirmed using in vitro assays. Results CELSR1, CELSR2 and CELSR3 genes were significantly clustered with rare driver coding mutations (q-value< 0.05) demonstrated by OncodriveCLUST. During the validation stage, the number of rare loss of function (LoF) variants in CELSR1 was significantly enriched in NTDs compared with the LoF counts in the ExAC database (p < 0.001). Functional studies indicated compound heterozygote variants of CELSR2 p.Thr2026Met and DVL3 p.Asp403Asn result in down regulation of PCP signals. Conclusions These data indicate rare damaging variants of the CELSR genes, identified in ~ 14% of NTD cases, are expected to be driver genes in the Wnt/PCP pathway. Compound damaging variants of CELSR genes and other Wnt/PCP genes, which were observed in 3.3% of the studied NTD cohort, are also expected to amplify these effects at the pathway level. Neural tube defects (dpeaa)DE-He213 PCP (planar cell polarity) (dpeaa)DE-He213 Wnt (dpeaa)DE-He213 Variant (dpeaa)DE-He213 CELSR (dpeaa)DE-He213 Lei, Yunping aut Cao, Xuanye aut Zheng, Yufang aut Wang, Fang aut Bao, Yihua aut Peng, Rui aut Finnell, Richard H. aut Zhang, Ting aut Wang, Hongyan (orcid)0000-0001-6662-5837 aut Enthalten in BMC medical genomics London : BioMed Central, 2008 11(2018), 1 vom: 04. Apr. (DE-627)559080824 (DE-600)2411865-5 1755-8794 nnns volume:11 year:2018 number:1 day:04 month:04 https://dx.doi.org/10.1186/s12920-018-0355-9 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2018 1 04 04
language	English
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spellingShingle	Chen, Zhongzhong misc Neural tube defects misc PCP (planar cell polarity) misc Wnt misc Variant misc CELSR Genetic analysis of Wnt/PCP genes in neural tube defects
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topic_title	Genetic analysis of Wnt/PCP genes in neural tube defects Neural tube defects (dpeaa)DE-He213 PCP (planar cell polarity) (dpeaa)DE-He213 Wnt (dpeaa)DE-He213 Variant (dpeaa)DE-He213 CELSR (dpeaa)DE-He213
topic	misc Neural tube defects misc PCP (planar cell polarity) misc Wnt misc Variant misc CELSR
topic_unstemmed	misc Neural tube defects misc PCP (planar cell polarity) misc Wnt misc Variant misc CELSR
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title	Genetic analysis of Wnt/PCP genes in neural tube defects
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title_full	Genetic analysis of Wnt/PCP genes in neural tube defects
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author_browse	Chen, Zhongzhong Lei, Yunping Cao, Xuanye Zheng, Yufang Wang, Fang Bao, Yihua Peng, Rui Finnell, Richard H. Zhang, Ting Wang, Hongyan
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title_sort	genetic analysis of wnt/pcp genes in neural tube defects
title_auth	Genetic analysis of Wnt/PCP genes in neural tube defects
abstract	Background Mouse homozygous mutants in Wnt/planar cell polarity (PCP) pathway genes have been shown to cause neural tube defects (NTDs) through the disruption of normal morphogenetic processes critical to neural tube closure (NTC). Knockout mice that are heterozygotes of single PCP genes likely fail to produce NTD phenotypes, yet damaging variants detected in human NTDs are almost always heterozygous, suggesting that other deleterious interacting variants are likely to be present. Nonetheless, the Wnt/PCP pathway remains a genetic hotspot. Addressing these issues is essential for understanding the genetic etiology of human NTDs. Methods We performed targeted next-generation sequencing (NGS) on 30 NTD-predisposing Wnt/PCP pathway genes in 184 Chinese NTD cases. We subsequently replicated our findings for the CELSR1 gene in an independent cohort of 292 Caucasian NTD samples from the USA. Functional validations were confirmed using in vitro assays. Results CELSR1, CELSR2 and CELSR3 genes were significantly clustered with rare driver coding mutations (q-value< 0.05) demonstrated by OncodriveCLUST. During the validation stage, the number of rare loss of function (LoF) variants in CELSR1 was significantly enriched in NTDs compared with the LoF counts in the ExAC database (p < 0.001). Functional studies indicated compound heterozygote variants of CELSR2 p.Thr2026Met and DVL3 p.Asp403Asn result in down regulation of PCP signals. Conclusions These data indicate rare damaging variants of the CELSR genes, identified in ~ 14% of NTD cases, are expected to be driver genes in the Wnt/PCP pathway. Compound damaging variants of CELSR genes and other Wnt/PCP genes, which were observed in 3.3% of the studied NTD cohort, are also expected to amplify these effects at the pathway level. © The Author(s). 2018
abstractGer	Background Mouse homozygous mutants in Wnt/planar cell polarity (PCP) pathway genes have been shown to cause neural tube defects (NTDs) through the disruption of normal morphogenetic processes critical to neural tube closure (NTC). Knockout mice that are heterozygotes of single PCP genes likely fail to produce NTD phenotypes, yet damaging variants detected in human NTDs are almost always heterozygous, suggesting that other deleterious interacting variants are likely to be present. Nonetheless, the Wnt/PCP pathway remains a genetic hotspot. Addressing these issues is essential for understanding the genetic etiology of human NTDs. Methods We performed targeted next-generation sequencing (NGS) on 30 NTD-predisposing Wnt/PCP pathway genes in 184 Chinese NTD cases. We subsequently replicated our findings for the CELSR1 gene in an independent cohort of 292 Caucasian NTD samples from the USA. Functional validations were confirmed using in vitro assays. Results CELSR1, CELSR2 and CELSR3 genes were significantly clustered with rare driver coding mutations (q-value< 0.05) demonstrated by OncodriveCLUST. During the validation stage, the number of rare loss of function (LoF) variants in CELSR1 was significantly enriched in NTDs compared with the LoF counts in the ExAC database (p < 0.001). Functional studies indicated compound heterozygote variants of CELSR2 p.Thr2026Met and DVL3 p.Asp403Asn result in down regulation of PCP signals. Conclusions These data indicate rare damaging variants of the CELSR genes, identified in ~ 14% of NTD cases, are expected to be driver genes in the Wnt/PCP pathway. Compound damaging variants of CELSR genes and other Wnt/PCP genes, which were observed in 3.3% of the studied NTD cohort, are also expected to amplify these effects at the pathway level. © The Author(s). 2018
abstract_unstemmed	Background Mouse homozygous mutants in Wnt/planar cell polarity (PCP) pathway genes have been shown to cause neural tube defects (NTDs) through the disruption of normal morphogenetic processes critical to neural tube closure (NTC). Knockout mice that are heterozygotes of single PCP genes likely fail to produce NTD phenotypes, yet damaging variants detected in human NTDs are almost always heterozygous, suggesting that other deleterious interacting variants are likely to be present. Nonetheless, the Wnt/PCP pathway remains a genetic hotspot. Addressing these issues is essential for understanding the genetic etiology of human NTDs. Methods We performed targeted next-generation sequencing (NGS) on 30 NTD-predisposing Wnt/PCP pathway genes in 184 Chinese NTD cases. We subsequently replicated our findings for the CELSR1 gene in an independent cohort of 292 Caucasian NTD samples from the USA. Functional validations were confirmed using in vitro assays. Results CELSR1, CELSR2 and CELSR3 genes were significantly clustered with rare driver coding mutations (q-value< 0.05) demonstrated by OncodriveCLUST. During the validation stage, the number of rare loss of function (LoF) variants in CELSR1 was significantly enriched in NTDs compared with the LoF counts in the ExAC database (p < 0.001). Functional studies indicated compound heterozygote variants of CELSR2 p.Thr2026Met and DVL3 p.Asp403Asn result in down regulation of PCP signals. Conclusions These data indicate rare damaging variants of the CELSR genes, identified in ~ 14% of NTD cases, are expected to be driver genes in the Wnt/PCP pathway. Compound damaging variants of CELSR genes and other Wnt/PCP genes, which were observed in 3.3% of the studied NTD cohort, are also expected to amplify these effects at the pathway level. © The Author(s). 2018
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author2	Lei, Yunping Cao, Xuanye Zheng, Yufang Wang, Fang Bao, Yihua Peng, Rui Finnell, Richard H. Zhang, Ting Wang, Hongyan
author2Str	Lei, Yunping Cao, Xuanye Zheng, Yufang Wang, Fang Bao, Yihua Peng, Rui Finnell, Richard H. Zhang, Ting Wang, Hongyan
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doi_str	10.1186/s12920-018-0355-9
up_date	2024-07-03T19:39:07.406Z
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Knockout mice that are heterozygotes of single PCP genes likely fail to produce NTD phenotypes, yet damaging variants detected in human NTDs are almost always heterozygous, suggesting that other deleterious interacting variants are likely to be present. Nonetheless, the Wnt/PCP pathway remains a genetic hotspot. Addressing these issues is essential for understanding the genetic etiology of human NTDs. Methods We performed targeted next-generation sequencing (NGS) on 30 NTD-predisposing Wnt/PCP pathway genes in 184 Chinese NTD cases. We subsequently replicated our findings for the CELSR1 gene in an independent cohort of 292 Caucasian NTD samples from the USA. Functional validations were confirmed using in vitro assays. Results CELSR1, CELSR2 and CELSR3 genes were significantly clustered with rare driver coding mutations (q-value< 0.05) demonstrated by OncodriveCLUST. During the validation stage, the number of rare loss of function (LoF) variants in CELSR1 was significantly enriched in NTDs compared with the LoF counts in the ExAC database (p < 0.001). Functional studies indicated compound heterozygote variants of CELSR2 p.Thr2026Met and DVL3 p.Asp403Asn result in down regulation of PCP signals. Conclusions These data indicate rare damaging variants of the CELSR genes, identified in ~ 14% of NTD cases, are expected to be driver genes in the Wnt/PCP pathway. 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Genetic analysis of Wnt/PCP genes in neural tube defects

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