Genetic architecture of laterality defects revealed by whole exome sequencing
Aberrant left-right patterning in the developing human embryo can lead to a broad spectrum of congenital malformations. The causes of most laterality defects are not known, with variants in established genes accounting for
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| Veröffentlicht in: | European journal of human genetics : EJHG 2019-04, Vol.27 (4), p.563-573 |
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| creator | Li, Alexander H Hanchard, Neil A Azamian, Mahshid D'Alessandro, Lisa C A Coban-Akdemir, Zeynep Lopez, Keila N Hall, Nancy J Dickerson, Heather Nicosia, Annarita Fernbach, Susan Boone, Philip M Gambin, Tomaz Karaca, Ender Gu, Shen Yuan, Bo Jhangiani, Shalini N Doddapaneni, HarshaVardhan Hu, Jianhong Dinh, Huyen Jayaseelan, Joy Muzny, Donna Lalani, Seema Towbin, Jeffrey Penny, Daniel Fraser, Charles Martin, James Lupski, James R Gibbs, Richard A Boerwinkle, Eric Ware, Stephanie M Belmont, John W |
| description | Aberrant left-right patterning in the developing human embryo can lead to a broad spectrum of congenital malformations. The causes of most laterality defects are not known, with variants in established genes accounting for |
| doi_str_mv | 10.1038/s41431-018-0307-z |
| format | Article |
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The causes of most laterality defects are not known, with variants in established genes accounting for <20% of cases. We sought to characterize the genetic spectrum of these conditions by performing whole-exome sequencing of 323 unrelated laterality cases. We investigated the role of rare, predicted-damaging variation in 1726 putative laterality candidate genes derived from model organisms, pathway analyses, and human phenotypes. We also evaluated the contribution of homo/hemizygous exon deletions and gene-based burden of rare variation. A total of 28 candidate variants (26 rare predicted-damaging variants and 2 hemizygous deletions) were identified, including variants in genes known to cause heterotaxy and primary ciliary dyskinesia (ACVR2B, NODAL, ZIC3, DNAI1, DNAH5, HYDIN, MMP21), and genes without a human phenotype association, but with prior evidence for a role in embryonic laterality or cardiac development. Sanger validation of the latter variants in probands and their parents revealed no de novo variants, but apparent transmitted heterozygous (ROCK2, ISL1, SMAD2), and hemizygous (RAI2, RIPPLY1) variant patterns. Collectively, these variants account for 7.1% of our study subjects. We also observe evidence for an excess burden of rare, predicted loss-of-function variation in PXDNL and BMS1- two genes relevant to the broader laterality phenotype. These findings highlight potential new genes in the development of laterality defects, and suggest extensive locus heterogeneity and complex genetic models in this class of birth defects.</description><identifier>ISSN: 1018-4813</identifier><identifier>EISSN: 1476-5438</identifier><identifier>DOI: 10.1038/s41431-018-0307-z</identifier><identifier>PMID: 30622330</identifier><language>eng</language><publisher>England: Nature Publishing Group</publisher><subject>Congenital defects ; Defects ; Embryogenesis ; Islet-1 protein ; Phenotypes ; Primary ciliary dyskinesia ; Smad2 protein ; Whole genome sequencing</subject><ispartof>European journal of human genetics : EJHG, 2019-04, Vol.27 (4), p.563-573</ispartof><rights>2019© European Society of Human Genetics 2019</rights><rights>European Society of Human Genetics 2019</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c493t-8bc4c6d25203e06fedf19c18fda07e67a9cbc9203567b41858148e65edfb64a03</citedby><cites>FETCH-LOGICAL-c493t-8bc4c6d25203e06fedf19c18fda07e67a9cbc9203567b41858148e65edfb64a03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460585/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460585/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27903,27904,53770,53772</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30622330$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Li, Alexander H</creatorcontrib><creatorcontrib>Hanchard, Neil A</creatorcontrib><creatorcontrib>Azamian, Mahshid</creatorcontrib><creatorcontrib>D'Alessandro, Lisa C A</creatorcontrib><creatorcontrib>Coban-Akdemir, Zeynep</creatorcontrib><creatorcontrib>Lopez, Keila N</creatorcontrib><creatorcontrib>Hall, Nancy J</creatorcontrib><creatorcontrib>Dickerson, Heather</creatorcontrib><creatorcontrib>Nicosia, Annarita</creatorcontrib><creatorcontrib>Fernbach, Susan</creatorcontrib><creatorcontrib>Boone, Philip M</creatorcontrib><creatorcontrib>Gambin, Tomaz</creatorcontrib><creatorcontrib>Karaca, Ender</creatorcontrib><creatorcontrib>Gu, Shen</creatorcontrib><creatorcontrib>Yuan, Bo</creatorcontrib><creatorcontrib>Jhangiani, Shalini N</creatorcontrib><creatorcontrib>Doddapaneni, HarshaVardhan</creatorcontrib><creatorcontrib>Hu, Jianhong</creatorcontrib><creatorcontrib>Dinh, Huyen</creatorcontrib><creatorcontrib>Jayaseelan, Joy</creatorcontrib><creatorcontrib>Muzny, Donna</creatorcontrib><creatorcontrib>Lalani, Seema</creatorcontrib><creatorcontrib>Towbin, Jeffrey</creatorcontrib><creatorcontrib>Penny, Daniel</creatorcontrib><creatorcontrib>Fraser, Charles</creatorcontrib><creatorcontrib>Martin, James</creatorcontrib><creatorcontrib>Lupski, James R</creatorcontrib><creatorcontrib>Gibbs, Richard A</creatorcontrib><creatorcontrib>Boerwinkle, Eric</creatorcontrib><creatorcontrib>Ware, Stephanie M</creatorcontrib><creatorcontrib>Belmont, John W</creatorcontrib><title>Genetic architecture of laterality defects revealed by whole exome sequencing</title><title>European journal of human genetics : EJHG</title><addtitle>Eur J Hum Genet</addtitle><description>Aberrant left-right patterning in the developing human embryo can lead to a broad spectrum of congenital malformations. The causes of most laterality defects are not known, with variants in established genes accounting for <20% of cases. We sought to characterize the genetic spectrum of these conditions by performing whole-exome sequencing of 323 unrelated laterality cases. We investigated the role of rare, predicted-damaging variation in 1726 putative laterality candidate genes derived from model organisms, pathway analyses, and human phenotypes. We also evaluated the contribution of homo/hemizygous exon deletions and gene-based burden of rare variation. A total of 28 candidate variants (26 rare predicted-damaging variants and 2 hemizygous deletions) were identified, including variants in genes known to cause heterotaxy and primary ciliary dyskinesia (ACVR2B, NODAL, ZIC3, DNAI1, DNAH5, HYDIN, MMP21), and genes without a human phenotype association, but with prior evidence for a role in embryonic laterality or cardiac development. Sanger validation of the latter variants in probands and their parents revealed no de novo variants, but apparent transmitted heterozygous (ROCK2, ISL1, SMAD2), and hemizygous (RAI2, RIPPLY1) variant patterns. Collectively, these variants account for 7.1% of our study subjects. We also observe evidence for an excess burden of rare, predicted loss-of-function variation in PXDNL and BMS1- two genes relevant to the broader laterality phenotype. These findings highlight potential new genes in the development of laterality defects, and suggest extensive locus heterogeneity and complex genetic models in this class of birth defects.</description><subject>Congenital defects</subject><subject>Defects</subject><subject>Embryogenesis</subject><subject>Islet-1 protein</subject><subject>Phenotypes</subject><subject>Primary ciliary dyskinesia</subject><subject>Smad2 protein</subject><subject>Whole genome 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Alexander H ; Hanchard, Neil A ; Azamian, Mahshid ; D'Alessandro, Lisa C A ; Coban-Akdemir, Zeynep ; Lopez, Keila N ; Hall, Nancy J ; Dickerson, Heather ; Nicosia, Annarita ; Fernbach, Susan ; Boone, Philip M ; Gambin, Tomaz ; Karaca, Ender ; Gu, Shen ; Yuan, Bo ; Jhangiani, Shalini N ; Doddapaneni, HarshaVardhan ; Hu, Jianhong ; Dinh, Huyen ; Jayaseelan, Joy ; Muzny, Donna ; Lalani, Seema ; Towbin, Jeffrey ; Penny, Daniel ; Fraser, Charles ; Martin, James ; Lupski, James R ; Gibbs, Richard A ; Boerwinkle, Eric ; Ware, Stephanie M ; Belmont, John W</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c493t-8bc4c6d25203e06fedf19c18fda07e67a9cbc9203567b41858148e65edfb64a03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Congenital defects</topic><topic>Defects</topic><topic>Embryogenesis</topic><topic>Islet-1 protein</topic><topic>Phenotypes</topic><topic>Primary ciliary 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revealed by whole exome sequencing</atitle><jtitle>European journal of human genetics : EJHG</jtitle><addtitle>Eur J Hum Genet</addtitle><date>2019-04-01</date><risdate>2019</risdate><volume>27</volume><issue>4</issue><spage>563</spage><epage>573</epage><pages>563-573</pages><issn>1018-4813</issn><eissn>1476-5438</eissn><abstract>Aberrant left-right patterning in the developing human embryo can lead to a broad spectrum of congenital malformations. The causes of most laterality defects are not known, with variants in established genes accounting for <20% of cases. We sought to characterize the genetic spectrum of these conditions by performing whole-exome sequencing of 323 unrelated laterality cases. We investigated the role of rare, predicted-damaging variation in 1726 putative laterality candidate genes derived from model organisms, pathway analyses, and human phenotypes. We also evaluated the contribution of homo/hemizygous exon deletions and gene-based burden of rare variation. A total of 28 candidate variants (26 rare predicted-damaging variants and 2 hemizygous deletions) were identified, including variants in genes known to cause heterotaxy and primary ciliary dyskinesia (ACVR2B, NODAL, ZIC3, DNAI1, DNAH5, HYDIN, MMP21), and genes without a human phenotype association, but with prior evidence for a role in embryonic laterality or cardiac development. Sanger validation of the latter variants in probands and their parents revealed no de novo variants, but apparent transmitted heterozygous (ROCK2, ISL1, SMAD2), and hemizygous (RAI2, RIPPLY1) variant patterns. Collectively, these variants account for 7.1% of our study subjects. We also observe evidence for an excess burden of rare, predicted loss-of-function variation in PXDNL and BMS1- two genes relevant to the broader laterality phenotype. These findings highlight potential new genes in the development of laterality defects, and suggest extensive locus heterogeneity and complex genetic models in this class of birth defects.</abstract><cop>England</cop><pub>Nature Publishing Group</pub><pmid>30622330</pmid><doi>10.1038/s41431-018-0307-z</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | European journal of human genetics : EJHG, 2019-04, Vol.27 (4), p.563-573 |
| issn | 1018-4813 1476-5438 |
| language | eng |
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| source | Springer Nature - Complete Springer Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | Congenital defects Defects Embryogenesis Islet-1 protein Phenotypes Primary ciliary dyskinesia Smad2 protein Whole genome sequencing |
| title | Genetic architecture of laterality defects revealed by whole exome sequencing |
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