C Identification of the major genetic contributors to tetralogy of fallot
There is strong evidence from familial recurrence studies for a genetic predisposition to sporadic, non-syndromic Tetralogy of Fallot (TOF). TOF is the most common, cyanotic congenital heart disease (CHD) phenotype yet the cause for the majority of cases remains elusive. Rare genetic variants have b...
Gespeichert in:
| Veröffentlicht in: | Heart (British Cardiac Society) 2019-05, Vol.105 (Suppl 6), p.A182 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | |
|---|---|
| container_issue | Suppl 6 |
| container_start_page | A182 |
| container_title | Heart (British Cardiac Society) |
| container_volume | 105 |
| creator | Page, Donna J Miossec, Matthieu J Williams, Simon G Monaghan, Richard M Fotiou, Elisavet Cordell, Heather J Sutcliffe, Louise Topf, Ana Bourgey, Mathieu Bourque, Guillaume Eveleigh, Robert Dunwoodie, Sally L Winlaw, David S Bhattacharya, Shoumo Breckpot, Jeroen Devriendt, Koenraad Gewillig, Marc Brook, David Setchfield, Kerry Bu’Lock, Frances A O’Sullivan, John Stuart, Graham Bezzina, Connie Mulder, Barbara JM Postma, Alex V Bentham, James R Baron, Martin Bhaskar, Sanjeev S Black, Graeme C Newman, William G Hentges, Kathryn E Lathrop, Mark Santibanez-Koref, Mauro Keavney, Bernard D |
| description | There is strong evidence from familial recurrence studies for a genetic predisposition to sporadic, non-syndromic Tetralogy of Fallot (TOF). TOF is the most common, cyanotic congenital heart disease (CHD) phenotype yet the cause for the majority of cases remains elusive. Rare genetic variants have been identified as important contributors to the risk of CHD, but relatively small numbers of TOF cases have been studied to date. 829 TOF patients underwent whole exome sequencing (WES), the largest cohort of non-syndromic TOF patients reported to date. The prevalence of unique, deleterious variants was determined; defined by their absence in the Genome Aggregation Database (gnomAD) and a scaled combined annotation-dependent depletion (CADD) score of ≥20. Clustering analysis of variants revealed that two genes, NOTCH1 and FLT4, surpassed thresholds for genome-wide significance (assigned as P |
| doi_str_mv | 10.1136/heartjnl-2019-BCS.226 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_bmj_p</sourceid><recordid>TN_cdi_proquest_journals_2230234919</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2230234919</sourcerecordid><originalsourceid>FETCH-LOGICAL-b1166-810af9edbc6aa8fff74b7f62de2a0c26bf859454b3d99db753b75c657565121c3</originalsourceid><addsrcrecordid>eNo1kM9KxDAQh4MouK4-ghDw3DV_mrQ5atF1ccGDCt5Ckia7Ld1mTdPD3rz4oj6JKauHYX4M38zAB8A1RguMKb_dWhVi23cZQVhk99XrghB-AmY45-U0-zhNmTKWcUSLc3AxDC1CKBcln4Hn6ufre1XbPjauMSo2vofewbi1cKdaH-DG9jY2Bhrfx9DoMfowwOhhtDGozm8OE-5U1_l4Cc5SGOzVX5-D98eHt-opW78sV9XdOtMYc56VGCknbK0NV6p0zhW5LhwntSUKGcK1K5nIWa5pLUStC0ZTGc4Kxhkm2NA5uDne3Qf_OdohytaPoU8vJSEUEZoLLBKFjpTetXIfmp0KB4mRnJTJf2VyUiaTsrTJ6S9CGWMf</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2230234919</pqid></control><display><type>article</type><title>C Identification of the major genetic contributors to tetralogy of fallot</title><source>PubMed Central</source><creator>Page, Donna J ; Miossec, Matthieu J ; Williams, Simon G ; Monaghan, Richard M ; Fotiou, Elisavet ; Cordell, Heather J ; Sutcliffe, Louise ; Topf, Ana ; Bourgey, Mathieu ; Bourque, Guillaume ; Eveleigh, Robert ; Dunwoodie, Sally L ; Winlaw, David S ; Bhattacharya, Shoumo ; Breckpot, Jeroen ; Devriendt, Koenraad ; Gewillig, Marc ; Brook, David ; Setchfield, Kerry ; Bu’Lock, Frances A ; O’Sullivan, John ; Stuart, Graham ; Bezzina, Connie ; Mulder, Barbara JM ; Postma, Alex V ; Bentham, James R ; Baron, Martin ; Bhaskar, Sanjeev S ; Black, Graeme C ; Newman, William G ; Hentges, Kathryn E ; Lathrop, Mark ; Santibanez-Koref, Mauro ; Keavney, Bernard D</creator><creatorcontrib>Page, Donna J ; Miossec, Matthieu J ; Williams, Simon G ; Monaghan, Richard M ; Fotiou, Elisavet ; Cordell, Heather J ; Sutcliffe, Louise ; Topf, Ana ; Bourgey, Mathieu ; Bourque, Guillaume ; Eveleigh, Robert ; Dunwoodie, Sally L ; Winlaw, David S ; Bhattacharya, Shoumo ; Breckpot, Jeroen ; Devriendt, Koenraad ; Gewillig, Marc ; Brook, David ; Setchfield, Kerry ; Bu’Lock, Frances A ; O’Sullivan, John ; Stuart, Graham ; Bezzina, Connie ; Mulder, Barbara JM ; Postma, Alex V ; Bentham, James R ; Baron, Martin ; Bhaskar, Sanjeev S ; Black, Graeme C ; Newman, William G ; Hentges, Kathryn E ; Lathrop, Mark ; Santibanez-Koref, Mauro ; Keavney, Bernard D</creatorcontrib><description>There is strong evidence from familial recurrence studies for a genetic predisposition to sporadic, non-syndromic Tetralogy of Fallot (TOF). TOF is the most common, cyanotic congenital heart disease (CHD) phenotype yet the cause for the majority of cases remains elusive. Rare genetic variants have been identified as important contributors to the risk of CHD, but relatively small numbers of TOF cases have been studied to date. 829 TOF patients underwent whole exome sequencing (WES), the largest cohort of non-syndromic TOF patients reported to date. The prevalence of unique, deleterious variants was determined; defined by their absence in the Genome Aggregation Database (gnomAD) and a scaled combined annotation-dependent depletion (CADD) score of ≥20. Clustering analysis of variants revealed that two genes, NOTCH1 and FLT4, surpassed thresholds for genome-wide significance (assigned as P<5 × 10-8), after correction for multiple comparisons. NOTCH1 was most frequently found to harbour unique, deleterious variants. 31 variants were observed in 37 probands (4.5%; 95% confidence interval [CI]: 3.2–6.1%) and included seven loss-of-function variants, 22 missense variants and two in-frame indels. Sanger sequencing of the unaffected parents of seven cases identified five de novo variants. Three NOTCH1 variants (p.G200R, p.C607Y and p.N1875S) were subjected to functional evaluation and two showed a reduction in Jagged1-induced NOTCH signalling. FLT4 variants were found in 2.4% (95% CI:1.6–3.8%) of TOF patients, with 21 patients harbouring 22 unique, deleterious variants. The variants identified were distinct to those that cause the congenital lymphoedema syndrome Milroy disease. In addition to NOTCH1, FLT4 and the well-established TOF gene, TBX1, we identified potential association with variants in several other biologically plausible candidate genes. In summary, the NOTCH1 locus is the most frequent site of genetic variants predisposing to non-syndromic TOF, followed by FLT4. Together, variants in these genes are found in almost 7% of TOF patients.</description><identifier>ISSN: 1355-6037</identifier><identifier>EISSN: 1468-201X</identifier><identifier>DOI: 10.1136/heartjnl-2019-BCS.226</identifier><language>eng</language><publisher>London: BMJ Publishing Group LTD</publisher><subject>Cardiovascular disease ; Congenital diseases ; Genomes</subject><ispartof>Heart (British Cardiac Society), 2019-05, Vol.105 (Suppl 6), p.A182</ispartof><rights>2019, 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</rights><rights>2019 2019, 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</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,777,781,27905,27906</link.rule.ids></links><search><creatorcontrib>Page, Donna J</creatorcontrib><creatorcontrib>Miossec, Matthieu J</creatorcontrib><creatorcontrib>Williams, Simon G</creatorcontrib><creatorcontrib>Monaghan, Richard M</creatorcontrib><creatorcontrib>Fotiou, Elisavet</creatorcontrib><creatorcontrib>Cordell, Heather J</creatorcontrib><creatorcontrib>Sutcliffe, Louise</creatorcontrib><creatorcontrib>Topf, Ana</creatorcontrib><creatorcontrib>Bourgey, Mathieu</creatorcontrib><creatorcontrib>Bourque, Guillaume</creatorcontrib><creatorcontrib>Eveleigh, Robert</creatorcontrib><creatorcontrib>Dunwoodie, Sally L</creatorcontrib><creatorcontrib>Winlaw, David S</creatorcontrib><creatorcontrib>Bhattacharya, Shoumo</creatorcontrib><creatorcontrib>Breckpot, Jeroen</creatorcontrib><creatorcontrib>Devriendt, Koenraad</creatorcontrib><creatorcontrib>Gewillig, Marc</creatorcontrib><creatorcontrib>Brook, David</creatorcontrib><creatorcontrib>Setchfield, Kerry</creatorcontrib><creatorcontrib>Bu’Lock, Frances A</creatorcontrib><creatorcontrib>O’Sullivan, John</creatorcontrib><creatorcontrib>Stuart, Graham</creatorcontrib><creatorcontrib>Bezzina, Connie</creatorcontrib><creatorcontrib>Mulder, Barbara JM</creatorcontrib><creatorcontrib>Postma, Alex V</creatorcontrib><creatorcontrib>Bentham, James R</creatorcontrib><creatorcontrib>Baron, Martin</creatorcontrib><creatorcontrib>Bhaskar, Sanjeev S</creatorcontrib><creatorcontrib>Black, Graeme C</creatorcontrib><creatorcontrib>Newman, William G</creatorcontrib><creatorcontrib>Hentges, Kathryn E</creatorcontrib><creatorcontrib>Lathrop, Mark</creatorcontrib><creatorcontrib>Santibanez-Koref, Mauro</creatorcontrib><creatorcontrib>Keavney, Bernard D</creatorcontrib><title>C Identification of the major genetic contributors to tetralogy of fallot</title><title>Heart (British Cardiac Society)</title><description>There is strong evidence from familial recurrence studies for a genetic predisposition to sporadic, non-syndromic Tetralogy of Fallot (TOF). TOF is the most common, cyanotic congenital heart disease (CHD) phenotype yet the cause for the majority of cases remains elusive. Rare genetic variants have been identified as important contributors to the risk of CHD, but relatively small numbers of TOF cases have been studied to date. 829 TOF patients underwent whole exome sequencing (WES), the largest cohort of non-syndromic TOF patients reported to date. The prevalence of unique, deleterious variants was determined; defined by their absence in the Genome Aggregation Database (gnomAD) and a scaled combined annotation-dependent depletion (CADD) score of ≥20. Clustering analysis of variants revealed that two genes, NOTCH1 and FLT4, surpassed thresholds for genome-wide significance (assigned as P<5 × 10-8), after correction for multiple comparisons. NOTCH1 was most frequently found to harbour unique, deleterious variants. 31 variants were observed in 37 probands (4.5%; 95% confidence interval [CI]: 3.2–6.1%) and included seven loss-of-function variants, 22 missense variants and two in-frame indels. Sanger sequencing of the unaffected parents of seven cases identified five de novo variants. Three NOTCH1 variants (p.G200R, p.C607Y and p.N1875S) were subjected to functional evaluation and two showed a reduction in Jagged1-induced NOTCH signalling. FLT4 variants were found in 2.4% (95% CI:1.6–3.8%) of TOF patients, with 21 patients harbouring 22 unique, deleterious variants. The variants identified were distinct to those that cause the congenital lymphoedema syndrome Milroy disease. In addition to NOTCH1, FLT4 and the well-established TOF gene, TBX1, we identified potential association with variants in several other biologically plausible candidate genes. In summary, the NOTCH1 locus is the most frequent site of genetic variants predisposing to non-syndromic TOF, followed by FLT4. Together, variants in these genes are found in almost 7% of TOF patients.</description><subject>Cardiovascular disease</subject><subject>Congenital diseases</subject><subject>Genomes</subject><issn>1355-6037</issn><issn>1468-201X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNo1kM9KxDAQh4MouK4-ghDw3DV_mrQ5atF1ccGDCt5Ckia7Ld1mTdPD3rz4oj6JKauHYX4M38zAB8A1RguMKb_dWhVi23cZQVhk99XrghB-AmY45-U0-zhNmTKWcUSLc3AxDC1CKBcln4Hn6ufre1XbPjauMSo2vofewbi1cKdaH-DG9jY2Bhrfx9DoMfowwOhhtDGozm8OE-5U1_l4Cc5SGOzVX5-D98eHt-opW78sV9XdOtMYc56VGCknbK0NV6p0zhW5LhwntSUKGcK1K5nIWa5pLUStC0ZTGc4Kxhkm2NA5uDne3Qf_OdohytaPoU8vJSEUEZoLLBKFjpTetXIfmp0KB4mRnJTJf2VyUiaTsrTJ6S9CGWMf</recordid><startdate>201905</startdate><enddate>201905</enddate><creator>Page, Donna J</creator><creator>Miossec, Matthieu J</creator><creator>Williams, Simon G</creator><creator>Monaghan, Richard M</creator><creator>Fotiou, Elisavet</creator><creator>Cordell, Heather J</creator><creator>Sutcliffe, Louise</creator><creator>Topf, Ana</creator><creator>Bourgey, Mathieu</creator><creator>Bourque, Guillaume</creator><creator>Eveleigh, Robert</creator><creator>Dunwoodie, Sally L</creator><creator>Winlaw, David S</creator><creator>Bhattacharya, Shoumo</creator><creator>Breckpot, Jeroen</creator><creator>Devriendt, Koenraad</creator><creator>Gewillig, Marc</creator><creator>Brook, David</creator><creator>Setchfield, Kerry</creator><creator>Bu’Lock, Frances A</creator><creator>O’Sullivan, John</creator><creator>Stuart, Graham</creator><creator>Bezzina, Connie</creator><creator>Mulder, Barbara JM</creator><creator>Postma, Alex V</creator><creator>Bentham, James R</creator><creator>Baron, Martin</creator><creator>Bhaskar, Sanjeev S</creator><creator>Black, Graeme C</creator><creator>Newman, William G</creator><creator>Hentges, Kathryn E</creator><creator>Lathrop, Mark</creator><creator>Santibanez-Koref, Mauro</creator><creator>Keavney, Bernard D</creator><general>BMJ Publishing Group LTD</general><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88I</scope><scope>8AF</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>BTHHO</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope></search><sort><creationdate>201905</creationdate><title>C Identification of the major genetic contributors to tetralogy of fallot</title><author>Page, Donna J ; Miossec, Matthieu J ; Williams, Simon G ; Monaghan, Richard M ; Fotiou, Elisavet ; Cordell, Heather J ; Sutcliffe, Louise ; Topf, Ana ; Bourgey, Mathieu ; Bourque, Guillaume ; Eveleigh, Robert ; Dunwoodie, Sally L ; Winlaw, David S ; Bhattacharya, Shoumo ; Breckpot, Jeroen ; Devriendt, Koenraad ; Gewillig, Marc ; Brook, David ; Setchfield, Kerry ; Bu’Lock, Frances A ; O’Sullivan, John ; Stuart, Graham ; Bezzina, Connie ; Mulder, Barbara JM ; Postma, Alex V ; Bentham, James R ; Baron, Martin ; Bhaskar, Sanjeev S ; Black, Graeme C ; Newman, William G ; Hentges, Kathryn E ; Lathrop, Mark ; Santibanez-Koref, Mauro ; Keavney, Bernard D</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-b1166-810af9edbc6aa8fff74b7f62de2a0c26bf859454b3d99db753b75c657565121c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Cardiovascular disease</topic><topic>Congenital diseases</topic><topic>Genomes</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Page, Donna J</creatorcontrib><creatorcontrib>Miossec, Matthieu J</creatorcontrib><creatorcontrib>Williams, Simon G</creatorcontrib><creatorcontrib>Monaghan, Richard M</creatorcontrib><creatorcontrib>Fotiou, Elisavet</creatorcontrib><creatorcontrib>Cordell, Heather J</creatorcontrib><creatorcontrib>Sutcliffe, Louise</creatorcontrib><creatorcontrib>Topf, Ana</creatorcontrib><creatorcontrib>Bourgey, Mathieu</creatorcontrib><creatorcontrib>Bourque, Guillaume</creatorcontrib><creatorcontrib>Eveleigh, Robert</creatorcontrib><creatorcontrib>Dunwoodie, Sally L</creatorcontrib><creatorcontrib>Winlaw, David S</creatorcontrib><creatorcontrib>Bhattacharya, Shoumo</creatorcontrib><creatorcontrib>Breckpot, Jeroen</creatorcontrib><creatorcontrib>Devriendt, Koenraad</creatorcontrib><creatorcontrib>Gewillig, Marc</creatorcontrib><creatorcontrib>Brook, David</creatorcontrib><creatorcontrib>Setchfield, Kerry</creatorcontrib><creatorcontrib>Bu’Lock, Frances A</creatorcontrib><creatorcontrib>O’Sullivan, John</creatorcontrib><creatorcontrib>Stuart, Graham</creatorcontrib><creatorcontrib>Bezzina, Connie</creatorcontrib><creatorcontrib>Mulder, Barbara JM</creatorcontrib><creatorcontrib>Postma, Alex V</creatorcontrib><creatorcontrib>Bentham, James R</creatorcontrib><creatorcontrib>Baron, Martin</creatorcontrib><creatorcontrib>Bhaskar, Sanjeev S</creatorcontrib><creatorcontrib>Black, Graeme C</creatorcontrib><creatorcontrib>Newman, William G</creatorcontrib><creatorcontrib>Hentges, Kathryn E</creatorcontrib><creatorcontrib>Lathrop, Mark</creatorcontrib><creatorcontrib>Santibanez-Koref, Mauro</creatorcontrib><creatorcontrib>Keavney, Bernard D</creatorcontrib><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>Science Database (Alumni Edition)</collection><collection>STEM Database</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 Essentials</collection><collection>ProQuest Central</collection><collection>BMJ Journals</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Science 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 Basic</collection><jtitle>Heart (British Cardiac Society)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Page, Donna J</au><au>Miossec, Matthieu J</au><au>Williams, Simon G</au><au>Monaghan, Richard M</au><au>Fotiou, Elisavet</au><au>Cordell, Heather J</au><au>Sutcliffe, Louise</au><au>Topf, Ana</au><au>Bourgey, Mathieu</au><au>Bourque, Guillaume</au><au>Eveleigh, Robert</au><au>Dunwoodie, Sally L</au><au>Winlaw, David S</au><au>Bhattacharya, Shoumo</au><au>Breckpot, Jeroen</au><au>Devriendt, Koenraad</au><au>Gewillig, Marc</au><au>Brook, David</au><au>Setchfield, Kerry</au><au>Bu’Lock, Frances A</au><au>O’Sullivan, John</au><au>Stuart, Graham</au><au>Bezzina, Connie</au><au>Mulder, Barbara JM</au><au>Postma, Alex V</au><au>Bentham, James R</au><au>Baron, Martin</au><au>Bhaskar, Sanjeev S</au><au>Black, Graeme C</au><au>Newman, William G</au><au>Hentges, Kathryn E</au><au>Lathrop, Mark</au><au>Santibanez-Koref, Mauro</au><au>Keavney, Bernard D</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>C Identification of the major genetic contributors to tetralogy of fallot</atitle><jtitle>Heart (British Cardiac Society)</jtitle><date>2019-05</date><risdate>2019</risdate><volume>105</volume><issue>Suppl 6</issue><spage>A182</spage><pages>A182-</pages><issn>1355-6037</issn><eissn>1468-201X</eissn><abstract>There is strong evidence from familial recurrence studies for a genetic predisposition to sporadic, non-syndromic Tetralogy of Fallot (TOF). TOF is the most common, cyanotic congenital heart disease (CHD) phenotype yet the cause for the majority of cases remains elusive. Rare genetic variants have been identified as important contributors to the risk of CHD, but relatively small numbers of TOF cases have been studied to date. 829 TOF patients underwent whole exome sequencing (WES), the largest cohort of non-syndromic TOF patients reported to date. The prevalence of unique, deleterious variants was determined; defined by their absence in the Genome Aggregation Database (gnomAD) and a scaled combined annotation-dependent depletion (CADD) score of ≥20. Clustering analysis of variants revealed that two genes, NOTCH1 and FLT4, surpassed thresholds for genome-wide significance (assigned as P<5 × 10-8), after correction for multiple comparisons. NOTCH1 was most frequently found to harbour unique, deleterious variants. 31 variants were observed in 37 probands (4.5%; 95% confidence interval [CI]: 3.2–6.1%) and included seven loss-of-function variants, 22 missense variants and two in-frame indels. Sanger sequencing of the unaffected parents of seven cases identified five de novo variants. Three NOTCH1 variants (p.G200R, p.C607Y and p.N1875S) were subjected to functional evaluation and two showed a reduction in Jagged1-induced NOTCH signalling. FLT4 variants were found in 2.4% (95% CI:1.6–3.8%) of TOF patients, with 21 patients harbouring 22 unique, deleterious variants. The variants identified were distinct to those that cause the congenital lymphoedema syndrome Milroy disease. In addition to NOTCH1, FLT4 and the well-established TOF gene, TBX1, we identified potential association with variants in several other biologically plausible candidate genes. In summary, the NOTCH1 locus is the most frequent site of genetic variants predisposing to non-syndromic TOF, followed by FLT4. Together, variants in these genes are found in almost 7% of TOF patients.</abstract><cop>London</cop><pub>BMJ Publishing Group LTD</pub><doi>10.1136/heartjnl-2019-BCS.226</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1355-6037 |
| ispartof | Heart (British Cardiac Society), 2019-05, Vol.105 (Suppl 6), p.A182 |
| issn | 1355-6037 1468-201X |
| language | eng |
| recordid | cdi_proquest_journals_2230234919 |
| source | PubMed Central |
| subjects | Cardiovascular disease Congenital diseases Genomes |
| title | C Identification of the major genetic contributors to tetralogy of fallot |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-18T04%3A12%3A08IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_bmj_p&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=C%E2%80%85Identification%20of%20the%20major%20genetic%20contributors%20to%20tetralogy%20of%20fallot&rft.jtitle=Heart%20(British%20Cardiac%20Society)&rft.au=Page,%20Donna%20J&rft.date=2019-05&rft.volume=105&rft.issue=Suppl%206&rft.spage=A182&rft.pages=A182-&rft.issn=1355-6037&rft.eissn=1468-201X&rft_id=info:doi/10.1136/heartjnl-2019-BCS.226&rft_dat=%3Cproquest_bmj_p%3E2230234919%3C/proquest_bmj_p%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2230234919&rft_id=info:pmid/&rfr_iscdi=true |