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Whole-exome sequencing points to considerable genetic heterogeneity of cerebral palsy
Cerebral palsy (CP) is a common, clinically heterogeneous group of disorders affecting movement and posture. Its prevalence has changed little in 50 years and the causes remain largely unknown. The genetic contribution to CP causation has been predicted to be ~2%. We performed whole-exome sequencing...
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| Published in: | Molecular psychiatry 2015-02, Vol.20 (2), p.176-182 |
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| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| container_title | Molecular psychiatry |
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| creator | McMichael, G Bainbridge, M N Haan, E Corbett, M Gardner, A Thompson, S van Bon, B W M van Eyk, C L Broadbent, J Reynolds, C O'Callaghan, M E Nguyen, L S Adelson, D L Russo, R Jhangiani, S Doddapaneni, H Muzny, D M Gibbs, R A Gecz, J MacLennan, A H |
| description | Cerebral palsy (CP) is a common, clinically heterogeneous group of disorders affecting movement and posture. Its prevalence has changed little in 50 years and the causes remain largely unknown. The genetic contribution to CP causation has been predicted to be ~2%. We performed whole-exome sequencing of 183 cases with CP including both parents (98 cases) or one parent (67 cases) and 18 singleton cases (no parental DNA). We identified and validated 61
de novo
protein-altering variants in 43 out of 98 (44%) case-parent trios. Initial prioritization of variants for causality was by mutation type, whether they were known or predicted to be deleterious and whether they occurred in known disease genes whose clinical spectrum overlaps CP. Further, prioritization used two multidimensional frameworks—the Residual Variation Intolerance Score and the Combined Annotation-dependent Depletion score. Ten
de novo
mutations in three previously identified disease genes (
TUBA1A
(
n
=2),
SCN8A
(
n
=1) and
KDM5C
(
n
=1)) and in six novel candidate CP genes (
AGAP1
,
JHDM1D
,
MAST1
,
NAA35
,
RFX2
and
WIPI2
) were predicted to be potentially pathogenic for CP. In addition, we identified four predicted pathogenic, hemizygous variants on chromosome X in two known disease genes,
L1CAM
and
PAK3,
and in two novel candidate CP genes,
CD99L2
and
TENM1
. In total, 14% of CP cases, by strict criteria, had a potentially disease-causing gene variant. Half were in novel genes. The genetic heterogeneity highlights the complexity of the genetic contribution to CP. Function and pathway studies are required to establish the causative role of these putative pathogenic CP genes. |
| doi_str_mv | 10.1038/mp.2014.189 |
| format | article |
| fullrecord | <record><control><sourceid>gale_proqu</sourceid><recordid>TN_cdi_proquest_miscellaneous_1683348193</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A404592216</galeid><sourcerecordid>A404592216</sourcerecordid><originalsourceid>FETCH-LOGICAL-c552t-3a725385afd8ac4dfa4f250c8ac199195917499cdaedf617e47edd57c7561a03</originalsourceid><addsrcrecordid>eNqNksuLFDEQh4Mo7rp68i4NXgTtMe90jsviCxa8rHgMmaQym6U7aZMe2PnvTTPrk0Ukh0qlvqpUFT-EnhO8IZgNb6d5QzHhGzLoB-iUcCV7IdTwsN2Z0D0nAz9BT2q9wXgNisfohAoppRLqFH35ep1H6OE2T9BV-LaH5GLadXOOaandkjuXU40eit2O0O0gwRJddw0LlLx6cTl0OXQOCmyLHbvZjvXwFD0KzcKzO3uGrt6_u7r42F9-_vDp4vyyd0LQpWdWUcEGYYMfrOM-WB6owK45RGuihSaKa-28BR8kUcAVeC-UU0ISi9kZenUsO5fcOq-LmWJ1MI42Qd5XQ-TAGB-IZv-BSswbzFRDX_6F3uR9SW0OQxkjsi1b8n9Ray1MhNb0F7WzI5iYQl6KdevX5pxjLjSlRDZqcw_Vjocptv1DiO39j4TXxwRXcq0FgplLnGw5GILNKgozzWYVhWmiaPSLu1b32wn8T_aHChrw5gjUFko7KL_Nck-97_cJvbQ</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1660015992</pqid></control><display><type>article</type><title>Whole-exome sequencing points to considerable genetic heterogeneity of cerebral palsy</title><source>Springer Link</source><creator>McMichael, G ; Bainbridge, M N ; Haan, E ; Corbett, M ; Gardner, A ; Thompson, S ; van Bon, B W M ; van Eyk, C L ; Broadbent, J ; Reynolds, C ; O'Callaghan, M E ; Nguyen, L S ; Adelson, D L ; Russo, R ; Jhangiani, S ; Doddapaneni, H ; Muzny, D M ; Gibbs, R A ; Gecz, J ; MacLennan, A H</creator><creatorcontrib>McMichael, G ; Bainbridge, M N ; Haan, E ; Corbett, M ; Gardner, A ; Thompson, S ; van Bon, B W M ; van Eyk, C L ; Broadbent, J ; Reynolds, C ; O'Callaghan, M E ; Nguyen, L S ; Adelson, D L ; Russo, R ; Jhangiani, S ; Doddapaneni, H ; Muzny, D M ; Gibbs, R A ; Gecz, J ; MacLennan, A H</creatorcontrib><description>Cerebral palsy (CP) is a common, clinically heterogeneous group of disorders affecting movement and posture. Its prevalence has changed little in 50 years and the causes remain largely unknown. The genetic contribution to CP causation has been predicted to be ~2%. We performed whole-exome sequencing of 183 cases with CP including both parents (98 cases) or one parent (67 cases) and 18 singleton cases (no parental DNA). We identified and validated 61
de novo
protein-altering variants in 43 out of 98 (44%) case-parent trios. Initial prioritization of variants for causality was by mutation type, whether they were known or predicted to be deleterious and whether they occurred in known disease genes whose clinical spectrum overlaps CP. Further, prioritization used two multidimensional frameworks—the Residual Variation Intolerance Score and the Combined Annotation-dependent Depletion score. Ten
de novo
mutations in three previously identified disease genes (
TUBA1A
(
n
=2),
SCN8A
(
n
=1) and
KDM5C
(
n
=1)) and in six novel candidate CP genes (
AGAP1
,
JHDM1D
,
MAST1
,
NAA35
,
RFX2
and
WIPI2
) were predicted to be potentially pathogenic for CP. In addition, we identified four predicted pathogenic, hemizygous variants on chromosome X in two known disease genes,
L1CAM
and
PAK3,
and in two novel candidate CP genes,
CD99L2
and
TENM1
. In total, 14% of CP cases, by strict criteria, had a potentially disease-causing gene variant. Half were in novel genes. The genetic heterogeneity highlights the complexity of the genetic contribution to CP. Function and pathway studies are required to establish the causative role of these putative pathogenic CP genes.</description><identifier>ISSN: 1359-4184</identifier><identifier>EISSN: 1476-5578</identifier><identifier>DOI: 10.1038/mp.2014.189</identifier><identifier>PMID: 25666757</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>45 ; 631/208 ; Adult ; Animals ; Autism ; Behavioral Sciences ; Biological Psychology ; Causation ; Cerebral palsy ; Cerebral Palsy - genetics ; Cohort Studies ; Deoxyribonucleic acid ; Depletion ; DNA ; Exome ; Exome sequencing ; Female ; Gene Library ; Gene mutation ; Genes ; Genetic aspects ; Genetic Heterogeneity ; Genetic Predisposition to Disease - genetics ; Genetic testing ; Genomes ; Gestational Age ; Health aspects ; Heterogeneity ; Hospitals ; Humans ; immediate-communication ; Intolerance ; Male ; Medicine ; Medicine & Public Health ; Mutation ; Neurosciences ; Paralysis ; Parents ; Parents & parenting ; Pediatrics ; Pharmacotherapy ; Posture ; Psychiatry ; Reproductive health ; Sequence Analysis, DNA ; Sodium channels (voltage-gated)</subject><ispartof>Molecular psychiatry, 2015-02, Vol.20 (2), p.176-182</ispartof><rights>Macmillan Publishers Limited 2015</rights><rights>COPYRIGHT 2015 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Feb 2015</rights><rights>Macmillan Publishers Limited 2015.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c552t-3a725385afd8ac4dfa4f250c8ac199195917499cdaedf617e47edd57c7561a03</citedby><cites>FETCH-LOGICAL-c552t-3a725385afd8ac4dfa4f250c8ac199195917499cdaedf617e47edd57c7561a03</cites><orcidid>0000-0002-7884-6861 ; 0000000278846861</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,783,787,27936,27937</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25666757$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>McMichael, G</creatorcontrib><creatorcontrib>Bainbridge, M N</creatorcontrib><creatorcontrib>Haan, E</creatorcontrib><creatorcontrib>Corbett, M</creatorcontrib><creatorcontrib>Gardner, A</creatorcontrib><creatorcontrib>Thompson, S</creatorcontrib><creatorcontrib>van Bon, B W M</creatorcontrib><creatorcontrib>van Eyk, C L</creatorcontrib><creatorcontrib>Broadbent, J</creatorcontrib><creatorcontrib>Reynolds, C</creatorcontrib><creatorcontrib>O'Callaghan, M E</creatorcontrib><creatorcontrib>Nguyen, L S</creatorcontrib><creatorcontrib>Adelson, D L</creatorcontrib><creatorcontrib>Russo, R</creatorcontrib><creatorcontrib>Jhangiani, S</creatorcontrib><creatorcontrib>Doddapaneni, H</creatorcontrib><creatorcontrib>Muzny, D M</creatorcontrib><creatorcontrib>Gibbs, R A</creatorcontrib><creatorcontrib>Gecz, J</creatorcontrib><creatorcontrib>MacLennan, A H</creatorcontrib><title>Whole-exome sequencing points to considerable genetic heterogeneity of cerebral palsy</title><title>Molecular psychiatry</title><addtitle>Mol Psychiatry</addtitle><addtitle>Mol Psychiatry</addtitle><description>Cerebral palsy (CP) is a common, clinically heterogeneous group of disorders affecting movement and posture. Its prevalence has changed little in 50 years and the causes remain largely unknown. The genetic contribution to CP causation has been predicted to be ~2%. We performed whole-exome sequencing of 183 cases with CP including both parents (98 cases) or one parent (67 cases) and 18 singleton cases (no parental DNA). We identified and validated 61
de novo
protein-altering variants in 43 out of 98 (44%) case-parent trios. Initial prioritization of variants for causality was by mutation type, whether they were known or predicted to be deleterious and whether they occurred in known disease genes whose clinical spectrum overlaps CP. Further, prioritization used two multidimensional frameworks—the Residual Variation Intolerance Score and the Combined Annotation-dependent Depletion score. Ten
de novo
mutations in three previously identified disease genes (
TUBA1A
(
n
=2),
SCN8A
(
n
=1) and
KDM5C
(
n
=1)) and in six novel candidate CP genes (
AGAP1
,
JHDM1D
,
MAST1
,
NAA35
,
RFX2
and
WIPI2
) were predicted to be potentially pathogenic for CP. In addition, we identified four predicted pathogenic, hemizygous variants on chromosome X in two known disease genes,
L1CAM
and
PAK3,
and in two novel candidate CP genes,
CD99L2
and
TENM1
. In total, 14% of CP cases, by strict criteria, had a potentially disease-causing gene variant. Half were in novel genes. The genetic heterogeneity highlights the complexity of the genetic contribution to CP. Function and pathway studies are required to establish the causative role of these putative pathogenic CP genes.</description><subject>45</subject><subject>631/208</subject><subject>Adult</subject><subject>Animals</subject><subject>Autism</subject><subject>Behavioral Sciences</subject><subject>Biological Psychology</subject><subject>Causation</subject><subject>Cerebral palsy</subject><subject>Cerebral Palsy - genetics</subject><subject>Cohort Studies</subject><subject>Deoxyribonucleic acid</subject><subject>Depletion</subject><subject>DNA</subject><subject>Exome</subject><subject>Exome sequencing</subject><subject>Female</subject><subject>Gene Library</subject><subject>Gene mutation</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Genetic Heterogeneity</subject><subject>Genetic Predisposition to Disease - genetics</subject><subject>Genetic testing</subject><subject>Genomes</subject><subject>Gestational Age</subject><subject>Health aspects</subject><subject>Heterogeneity</subject><subject>Hospitals</subject><subject>Humans</subject><subject>immediate-communication</subject><subject>Intolerance</subject><subject>Male</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mutation</subject><subject>Neurosciences</subject><subject>Paralysis</subject><subject>Parents</subject><subject>Parents & parenting</subject><subject>Pediatrics</subject><subject>Pharmacotherapy</subject><subject>Posture</subject><subject>Psychiatry</subject><subject>Reproductive health</subject><subject>Sequence Analysis, DNA</subject><subject>Sodium channels 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sequencing points to considerable genetic heterogeneity of cerebral palsy</title><author>McMichael, G ; Bainbridge, M N ; Haan, E ; Corbett, M ; Gardner, A ; Thompson, S ; van Bon, B W M ; van Eyk, C L ; Broadbent, J ; Reynolds, C ; O'Callaghan, M E ; Nguyen, L S ; Adelson, D L ; Russo, R ; Jhangiani, S ; Doddapaneni, H ; Muzny, D M ; Gibbs, R A ; Gecz, J ; MacLennan, A H</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c552t-3a725385afd8ac4dfa4f250c8ac199195917499cdaedf617e47edd57c7561a03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>45</topic><topic>631/208</topic><topic>Adult</topic><topic>Animals</topic><topic>Autism</topic><topic>Behavioral Sciences</topic><topic>Biological Psychology</topic><topic>Causation</topic><topic>Cerebral palsy</topic><topic>Cerebral Palsy - genetics</topic><topic>Cohort Studies</topic><topic>Deoxyribonucleic acid</topic><topic>Depletion</topic><topic>DNA</topic><topic>Exome</topic><topic>Exome sequencing</topic><topic>Female</topic><topic>Gene Library</topic><topic>Gene mutation</topic><topic>Genes</topic><topic>Genetic aspects</topic><topic>Genetic Heterogeneity</topic><topic>Genetic Predisposition to Disease - genetics</topic><topic>Genetic testing</topic><topic>Genomes</topic><topic>Gestational Age</topic><topic>Health aspects</topic><topic>Heterogeneity</topic><topic>Hospitals</topic><topic>Humans</topic><topic>immediate-communication</topic><topic>Intolerance</topic><topic>Male</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Mutation</topic><topic>Neurosciences</topic><topic>Paralysis</topic><topic>Parents</topic><topic>Parents & parenting</topic><topic>Pediatrics</topic><topic>Pharmacotherapy</topic><topic>Posture</topic><topic>Psychiatry</topic><topic>Reproductive health</topic><topic>Sequence Analysis, DNA</topic><topic>Sodium channels 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S</au><au>Doddapaneni, H</au><au>Muzny, D M</au><au>Gibbs, R A</au><au>Gecz, J</au><au>MacLennan, A H</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Whole-exome sequencing points to considerable genetic heterogeneity of cerebral palsy</atitle><jtitle>Molecular psychiatry</jtitle><stitle>Mol Psychiatry</stitle><addtitle>Mol Psychiatry</addtitle><date>2015-02-01</date><risdate>2015</risdate><volume>20</volume><issue>2</issue><spage>176</spage><epage>182</epage><pages>176-182</pages><issn>1359-4184</issn><eissn>1476-5578</eissn><abstract>Cerebral palsy (CP) is a common, clinically heterogeneous group of disorders affecting movement and posture. Its prevalence has changed little in 50 years and the causes remain largely unknown. The genetic contribution to CP causation has been predicted to be ~2%. We performed whole-exome sequencing of 183 cases with CP including both parents (98 cases) or one parent (67 cases) and 18 singleton cases (no parental DNA). We identified and validated 61
de novo
protein-altering variants in 43 out of 98 (44%) case-parent trios. Initial prioritization of variants for causality was by mutation type, whether they were known or predicted to be deleterious and whether they occurred in known disease genes whose clinical spectrum overlaps CP. Further, prioritization used two multidimensional frameworks—the Residual Variation Intolerance Score and the Combined Annotation-dependent Depletion score. Ten
de novo
mutations in three previously identified disease genes (
TUBA1A
(
n
=2),
SCN8A
(
n
=1) and
KDM5C
(
n
=1)) and in six novel candidate CP genes (
AGAP1
,
JHDM1D
,
MAST1
,
NAA35
,
RFX2
and
WIPI2
) were predicted to be potentially pathogenic for CP. In addition, we identified four predicted pathogenic, hemizygous variants on chromosome X in two known disease genes,
L1CAM
and
PAK3,
and in two novel candidate CP genes,
CD99L2
and
TENM1
. In total, 14% of CP cases, by strict criteria, had a potentially disease-causing gene variant. Half were in novel genes. The genetic heterogeneity highlights the complexity of the genetic contribution to CP. Function and pathway studies are required to establish the causative role of these putative pathogenic CP genes.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>25666757</pmid><doi>10.1038/mp.2014.189</doi><tpages>7</tpages><orcidid>https://orcid.org/0000-0002-7884-6861</orcidid><orcidid>https://orcid.org/0000000278846861</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1359-4184 |
| ispartof | Molecular psychiatry, 2015-02, Vol.20 (2), p.176-182 |
| issn | 1359-4184 1476-5578 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1683348193 |
| source | Springer Link |
| subjects | 45 631/208 Adult Animals Autism Behavioral Sciences Biological Psychology Causation Cerebral palsy Cerebral Palsy - genetics Cohort Studies Deoxyribonucleic acid Depletion DNA Exome Exome sequencing Female Gene Library Gene mutation Genes Genetic aspects Genetic Heterogeneity Genetic Predisposition to Disease - genetics Genetic testing Genomes Gestational Age Health aspects Heterogeneity Hospitals Humans immediate-communication Intolerance Male Medicine Medicine & Public Health Mutation Neurosciences Paralysis Parents Parents & parenting Pediatrics Pharmacotherapy Posture Psychiatry Reproductive health Sequence Analysis, DNA Sodium channels (voltage-gated) |
| title | Whole-exome sequencing points to considerable genetic heterogeneity of cerebral palsy |
| url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-11-13T08%3A51%3A55IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Whole-exome%20sequencing%20points%20to%20considerable%20genetic%20heterogeneity%20of%20cerebral%20palsy&rft.jtitle=Molecular%20psychiatry&rft.au=McMichael,%20G&rft.date=2015-02-01&rft.volume=20&rft.issue=2&rft.spage=176&rft.epage=182&rft.pages=176-182&rft.issn=1359-4184&rft.eissn=1476-5578&rft_id=info:doi/10.1038/mp.2014.189&rft_dat=%3Cgale_proqu%3EA404592216%3C/gale_proqu%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c552t-3a725385afd8ac4dfa4f250c8ac199195917499cdaedf617e47edd57c7561a03%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=1660015992&rft_id=info:pmid/25666757&rft_galeid=A404592216&rfr_iscdi=true |