Genomic mosaicism in the pathogenesis and inheritance of a Rett syndrome cohort
Purpose To determine the role of mosaicism in the pathogenesis and inheritance of Rett and Rett-like disorders. Methods We recruited 471 Rett and Rett-like patients. Panel-sequencing targeting MECP2 , CDKL5 , and FOXG1 was performed. Mosaicism was quantified in 147 patients by a Bayesian genotyper....
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| Veröffentlicht in: | Genetics in medicine 2019-06, Vol.21 (6), p.1330-1338 |
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| creator | Zhang, Qingping Yang, Xiaoxu Wang, Jiaping Li, Jiarui Wu, Qixi Wen, Yongxin Zhao, Ying Zhang, Xiaoying Yao, He Wu, Xiru Yu, Shujie Wei, Liping Bao, Xinhua |
| description | Purpose
To determine the role of mosaicism in the pathogenesis and inheritance of Rett and Rett-like disorders.
Methods
We recruited 471 Rett and Rett-like patients. Panel-sequencing targeting
MECP2
,
CDKL5
, and
FOXG1
was performed. Mosaicism was quantified in 147 patients by a Bayesian genotyper. Candidates were validated by amplicon sequencing and digital PCR. Germline mosaicism of 21 fathers with daughters carrying pathogenic
MECP2
variants was further quantified.
Results
Pathogenic variants of
MECP2/CDKL5
/
FOXG1
were found in 324/471 (68.7%) patients. Somatic
MECP2
mosaicism was confirmed in 5/471 (1.1%) patients, including 3/18 males (16.7%) and 2/453 females (0.4%). Three of the five patients with somatic
MECP2
mosaicism had mosaicism at MECP2-Arg106. Germline
MECP2
mosaicism was detected in 5/21 (23.8%) fathers.
Conclusion
This is the first systematic screening of somatic and paternal germline
MECP2
mosaicism at a cohort level. Our findings indicate that somatic
MECP2
mosaicism contributes directly to the pathogenicity of Rett syndrome, especially in male patients. MECP2-Arg106 might be a mosaic hotspot. The high proportion of paternal germline
MECP2
mosaicism indicates an underestimated mechanism underlying the paternal origin bias of
MECP2
variants. Finally, this study provides an empirical foundation for future studies of genetic disorders caused by de novo variations of strong paternal origin. |
| doi_str_mv | 10.1038/s41436-018-0348-2 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6752670</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2131233870</sourcerecordid><originalsourceid>FETCH-LOGICAL-c536t-8abf623f36566c6c884c2cca83ef607c869df411650453bbe7c4fcd03f5881fc3</originalsourceid><addsrcrecordid>eNp1kU1rVDEUhoMotlZ_gBsJuHFz9SQnyc1sBCnaCoWC6DpkcpO5KXOTMckI_ffNOLV-gKt8nOe8yeEh5CWDtwxQv6uCCVQDMD0ACj3wR-SUSYR-Uupx38NKD6gATsizWm8A2IgcnpITBAGSgz4l1xc-5SU6uuRqo4t1oTHRNnu6s23OG598jZXaNPX72ZfYbHKe5kAt_eJbo_U2TSUvnro859KekyfBbqt_cb-ekW-fPn49vxyuri8-n3-4GpxE1QZt10FxDKikUk45rYXjzlmNPigYnVarKQjGlAQhcb32oxPBTYBBas2CwzPy_pi7268XPzmfWrFbsytxseXWZBvN35UUZ7PJP4waJVcj9IA39wElf9_72swSq_PbrU0-76vhDBlH1D_R1_-gN3lfUh_PcI5CKLlaHSh2pFzJtRYfHj7DwBx0maMu03WZgy7De8-rP6d46PjlpwP8CNReShtffj_9_9Q7At2gog</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2234465990</pqid></control><display><type>article</type><title>Genomic mosaicism in the pathogenesis and inheritance of a Rett syndrome cohort</title><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Alma/SFX Local Collection</source><creator>Zhang, Qingping ; Yang, Xiaoxu ; Wang, Jiaping ; Li, Jiarui ; Wu, Qixi ; Wen, Yongxin ; Zhao, Ying ; Zhang, Xiaoying ; Yao, He ; Wu, Xiru ; Yu, Shujie ; Wei, Liping ; Bao, Xinhua</creator><creatorcontrib>Zhang, Qingping ; Yang, Xiaoxu ; Wang, Jiaping ; Li, Jiarui ; Wu, Qixi ; Wen, Yongxin ; Zhao, Ying ; Zhang, Xiaoying ; Yao, He ; Wu, Xiru ; Yu, Shujie ; Wei, Liping ; Bao, Xinhua</creatorcontrib><description>Purpose
To determine the role of mosaicism in the pathogenesis and inheritance of Rett and Rett-like disorders.
Methods
We recruited 471 Rett and Rett-like patients. Panel-sequencing targeting
MECP2
,
CDKL5
, and
FOXG1
was performed. Mosaicism was quantified in 147 patients by a Bayesian genotyper. Candidates were validated by amplicon sequencing and digital PCR. Germline mosaicism of 21 fathers with daughters carrying pathogenic
MECP2
variants was further quantified.
Results
Pathogenic variants of
MECP2/CDKL5
/
FOXG1
were found in 324/471 (68.7%) patients. Somatic
MECP2
mosaicism was confirmed in 5/471 (1.1%) patients, including 3/18 males (16.7%) and 2/453 females (0.4%). Three of the five patients with somatic
MECP2
mosaicism had mosaicism at MECP2-Arg106. Germline
MECP2
mosaicism was detected in 5/21 (23.8%) fathers.
Conclusion
This is the first systematic screening of somatic and paternal germline
MECP2
mosaicism at a cohort level. Our findings indicate that somatic
MECP2
mosaicism contributes directly to the pathogenicity of Rett syndrome, especially in male patients. MECP2-Arg106 might be a mosaic hotspot. The high proportion of paternal germline
MECP2
mosaicism indicates an underestimated mechanism underlying the paternal origin bias of
MECP2
variants. Finally, this study provides an empirical foundation for future studies of genetic disorders caused by de novo variations of strong paternal origin.</description><identifier>ISSN: 1098-3600</identifier><identifier>EISSN: 1530-0366</identifier><identifier>DOI: 10.1038/s41436-018-0348-2</identifier><identifier>PMID: 30405208</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>Adult ; Bayes Theorem ; Biomedical and Life Sciences ; Biomedicine ; Child, Preschool ; Cohort Studies ; Databases, Genetic ; Fathers ; Female ; Forkhead Transcription Factors - genetics ; Genomics ; Genotype ; Germ-Line Mutation - genetics ; Heredity ; Human Genetics ; Humans ; Laboratory Medicine ; Male ; Methyl-CpG-Binding Protein 2 - genetics ; Mosaicism ; Mutation ; Nerve Tissue Proteins - genetics ; Pathogenesis ; Protein Serine-Threonine Kinases - genetics ; Rett Syndrome - genetics ; Rett Syndrome - physiopathology</subject><ispartof>Genetics in medicine, 2019-06, Vol.21 (6), p.1330-1338</ispartof><rights>The Author(s) 2018</rights><rights>2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c536t-8abf623f36566c6c884c2cca83ef607c869df411650453bbe7c4fcd03f5881fc3</citedby><cites>FETCH-LOGICAL-c536t-8abf623f36566c6c884c2cca83ef607c869df411650453bbe7c4fcd03f5881fc3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30405208$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhang, Qingping</creatorcontrib><creatorcontrib>Yang, Xiaoxu</creatorcontrib><creatorcontrib>Wang, Jiaping</creatorcontrib><creatorcontrib>Li, Jiarui</creatorcontrib><creatorcontrib>Wu, Qixi</creatorcontrib><creatorcontrib>Wen, Yongxin</creatorcontrib><creatorcontrib>Zhao, Ying</creatorcontrib><creatorcontrib>Zhang, Xiaoying</creatorcontrib><creatorcontrib>Yao, He</creatorcontrib><creatorcontrib>Wu, Xiru</creatorcontrib><creatorcontrib>Yu, Shujie</creatorcontrib><creatorcontrib>Wei, Liping</creatorcontrib><creatorcontrib>Bao, Xinhua</creatorcontrib><title>Genomic mosaicism in the pathogenesis and inheritance of a Rett syndrome cohort</title><title>Genetics in medicine</title><addtitle>Genet Med</addtitle><addtitle>Genet Med</addtitle><description>Purpose
To determine the role of mosaicism in the pathogenesis and inheritance of Rett and Rett-like disorders.
Methods
We recruited 471 Rett and Rett-like patients. Panel-sequencing targeting
MECP2
,
CDKL5
, and
FOXG1
was performed. Mosaicism was quantified in 147 patients by a Bayesian genotyper. Candidates were validated by amplicon sequencing and digital PCR. Germline mosaicism of 21 fathers with daughters carrying pathogenic
MECP2
variants was further quantified.
Results
Pathogenic variants of
MECP2/CDKL5
/
FOXG1
were found in 324/471 (68.7%) patients. Somatic
MECP2
mosaicism was confirmed in 5/471 (1.1%) patients, including 3/18 males (16.7%) and 2/453 females (0.4%). Three of the five patients with somatic
MECP2
mosaicism had mosaicism at MECP2-Arg106. Germline
MECP2
mosaicism was detected in 5/21 (23.8%) fathers.
Conclusion
This is the first systematic screening of somatic and paternal germline
MECP2
mosaicism at a cohort level. Our findings indicate that somatic
MECP2
mosaicism contributes directly to the pathogenicity of Rett syndrome, especially in male patients. MECP2-Arg106 might be a mosaic hotspot. The high proportion of paternal germline
MECP2
mosaicism indicates an underestimated mechanism underlying the paternal origin bias of
MECP2
variants. Finally, this study provides an empirical foundation for future studies of genetic disorders caused by de novo variations of strong paternal origin.</description><subject>Adult</subject><subject>Bayes Theorem</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Child, Preschool</subject><subject>Cohort Studies</subject><subject>Databases, Genetic</subject><subject>Fathers</subject><subject>Female</subject><subject>Forkhead Transcription Factors - genetics</subject><subject>Genomics</subject><subject>Genotype</subject><subject>Germ-Line Mutation - genetics</subject><subject>Heredity</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Laboratory Medicine</subject><subject>Male</subject><subject>Methyl-CpG-Binding Protein 2 - genetics</subject><subject>Mosaicism</subject><subject>Mutation</subject><subject>Nerve Tissue Proteins - genetics</subject><subject>Pathogenesis</subject><subject>Protein Serine-Threonine Kinases - genetics</subject><subject>Rett Syndrome - genetics</subject><subject>Rett Syndrome - physiopathology</subject><issn>1098-3600</issn><issn>1530-0366</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp1kU1rVDEUhoMotlZ_gBsJuHFz9SQnyc1sBCnaCoWC6DpkcpO5KXOTMckI_ffNOLV-gKt8nOe8yeEh5CWDtwxQv6uCCVQDMD0ACj3wR-SUSYR-Uupx38NKD6gATsizWm8A2IgcnpITBAGSgz4l1xc-5SU6uuRqo4t1oTHRNnu6s23OG598jZXaNPX72ZfYbHKe5kAt_eJbo_U2TSUvnro859KekyfBbqt_cb-ekW-fPn49vxyuri8-n3-4GpxE1QZt10FxDKikUk45rYXjzlmNPigYnVarKQjGlAQhcb32oxPBTYBBas2CwzPy_pi7268XPzmfWrFbsytxseXWZBvN35UUZ7PJP4waJVcj9IA39wElf9_72swSq_PbrU0-76vhDBlH1D_R1_-gN3lfUh_PcI5CKLlaHSh2pFzJtRYfHj7DwBx0maMu03WZgy7De8-rP6d46PjlpwP8CNReShtffj_9_9Q7At2gog</recordid><startdate>20190601</startdate><enddate>20190601</enddate><creator>Zhang, Qingping</creator><creator>Yang, Xiaoxu</creator><creator>Wang, Jiaping</creator><creator>Li, Jiarui</creator><creator>Wu, Qixi</creator><creator>Wen, Yongxin</creator><creator>Zhao, Ying</creator><creator>Zhang, Xiaoying</creator><creator>Yao, He</creator><creator>Wu, Xiru</creator><creator>Yu, Shujie</creator><creator>Wei, Liping</creator><creator>Bao, Xinhua</creator><general>Nature Publishing Group US</general><general>Elsevier Limited</general><scope>C6C</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20190601</creationdate><title>Genomic mosaicism in the pathogenesis and inheritance of a Rett syndrome cohort</title><author>Zhang, Qingping ; Yang, Xiaoxu ; Wang, Jiaping ; Li, Jiarui ; Wu, Qixi ; Wen, Yongxin ; Zhao, Ying ; Zhang, Xiaoying ; Yao, He ; Wu, Xiru ; Yu, Shujie ; Wei, Liping ; Bao, Xinhua</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c536t-8abf623f36566c6c884c2cca83ef607c869df411650453bbe7c4fcd03f5881fc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Adult</topic><topic>Bayes Theorem</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Child, Preschool</topic><topic>Cohort Studies</topic><topic>Databases, Genetic</topic><topic>Fathers</topic><topic>Female</topic><topic>Forkhead Transcription Factors - genetics</topic><topic>Genomics</topic><topic>Genotype</topic><topic>Germ-Line Mutation - genetics</topic><topic>Heredity</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>Laboratory Medicine</topic><topic>Male</topic><topic>Methyl-CpG-Binding Protein 2 - genetics</topic><topic>Mosaicism</topic><topic>Mutation</topic><topic>Nerve Tissue Proteins - genetics</topic><topic>Pathogenesis</topic><topic>Protein Serine-Threonine Kinases - genetics</topic><topic>Rett Syndrome - genetics</topic><topic>Rett Syndrome - physiopathology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhang, Qingping</creatorcontrib><creatorcontrib>Yang, Xiaoxu</creatorcontrib><creatorcontrib>Wang, Jiaping</creatorcontrib><creatorcontrib>Li, Jiarui</creatorcontrib><creatorcontrib>Wu, Qixi</creatorcontrib><creatorcontrib>Wen, Yongxin</creatorcontrib><creatorcontrib>Zhao, Ying</creatorcontrib><creatorcontrib>Zhang, Xiaoying</creatorcontrib><creatorcontrib>Yao, He</creatorcontrib><creatorcontrib>Wu, Xiru</creatorcontrib><creatorcontrib>Yu, Shujie</creatorcontrib><creatorcontrib>Wei, Liping</creatorcontrib><creatorcontrib>Bao, Xinhua</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Genetics in medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhang, Qingping</au><au>Yang, Xiaoxu</au><au>Wang, Jiaping</au><au>Li, Jiarui</au><au>Wu, Qixi</au><au>Wen, Yongxin</au><au>Zhao, Ying</au><au>Zhang, Xiaoying</au><au>Yao, He</au><au>Wu, Xiru</au><au>Yu, Shujie</au><au>Wei, Liping</au><au>Bao, Xinhua</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Genomic mosaicism in the pathogenesis and inheritance of a Rett syndrome cohort</atitle><jtitle>Genetics in medicine</jtitle><stitle>Genet Med</stitle><addtitle>Genet Med</addtitle><date>2019-06-01</date><risdate>2019</risdate><volume>21</volume><issue>6</issue><spage>1330</spage><epage>1338</epage><pages>1330-1338</pages><issn>1098-3600</issn><eissn>1530-0366</eissn><abstract>Purpose
To determine the role of mosaicism in the pathogenesis and inheritance of Rett and Rett-like disorders.
Methods
We recruited 471 Rett and Rett-like patients. Panel-sequencing targeting
MECP2
,
CDKL5
, and
FOXG1
was performed. Mosaicism was quantified in 147 patients by a Bayesian genotyper. Candidates were validated by amplicon sequencing and digital PCR. Germline mosaicism of 21 fathers with daughters carrying pathogenic
MECP2
variants was further quantified.
Results
Pathogenic variants of
MECP2/CDKL5
/
FOXG1
were found in 324/471 (68.7%) patients. Somatic
MECP2
mosaicism was confirmed in 5/471 (1.1%) patients, including 3/18 males (16.7%) and 2/453 females (0.4%). Three of the five patients with somatic
MECP2
mosaicism had mosaicism at MECP2-Arg106. Germline
MECP2
mosaicism was detected in 5/21 (23.8%) fathers.
Conclusion
This is the first systematic screening of somatic and paternal germline
MECP2
mosaicism at a cohort level. Our findings indicate that somatic
MECP2
mosaicism contributes directly to the pathogenicity of Rett syndrome, especially in male patients. MECP2-Arg106 might be a mosaic hotspot. The high proportion of paternal germline
MECP2
mosaicism indicates an underestimated mechanism underlying the paternal origin bias of
MECP2
variants. Finally, this study provides an empirical foundation for future studies of genetic disorders caused by de novo variations of strong paternal origin.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>30405208</pmid><doi>10.1038/s41436-018-0348-2</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Genetics in medicine, 2019-06, Vol.21 (6), p.1330-1338 |
| issn | 1098-3600 1530-0366 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6752670 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Adult Bayes Theorem Biomedical and Life Sciences Biomedicine Child, Preschool Cohort Studies Databases, Genetic Fathers Female Forkhead Transcription Factors - genetics Genomics Genotype Germ-Line Mutation - genetics Heredity Human Genetics Humans Laboratory Medicine Male Methyl-CpG-Binding Protein 2 - genetics Mosaicism Mutation Nerve Tissue Proteins - genetics Pathogenesis Protein Serine-Threonine Kinases - genetics Rett Syndrome - genetics Rett Syndrome - physiopathology |
| title | Genomic mosaicism in the pathogenesis and inheritance of a Rett syndrome cohort |
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