Comprehensive whole genome sequence analyses yields novel genetic and structural insights for Intellectual Disability
<h3>Background</h3><p dir="ltr">Intellectual Disability (ID) is among the most common global disorders, yet etiology is unknown in ~30% of patients despite clinical assessment. Whole genome sequencing (WGS) is able to interrogate the entire genome, providing potential to...
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2017
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| author | Farah R. Zahir (18892108) |
| author2 | Jill C. Mwenifumbo (19725358) Hye-Jung E. Chun (19725361) Emilia L. Lim (3348266) Clara D. M. Van Karnebeek (19725364) Madeline Couse (3385817) Karen L. Mungall (9709370) Leora Lee (3214851) Nancy Makela (4046018) Linlea Armstrong (4046036) Cornelius F. Boerkoel (12242496) Sylvie L. Langlois (19725367) Barbara M. McGillivray (19725370) Steven J. M. Jones (9709382) Jan M. Friedman (11252261) Marco A. Marra (7610399) |
| author2_role | author author author author author author author author author author author author author author author |
| author_facet | Farah R. Zahir (18892108) Jill C. Mwenifumbo (19725358) Hye-Jung E. Chun (19725361) Emilia L. Lim (3348266) Clara D. M. Van Karnebeek (19725364) Madeline Couse (3385817) Karen L. Mungall (9709370) Leora Lee (3214851) Nancy Makela (4046018) Linlea Armstrong (4046036) Cornelius F. Boerkoel (12242496) Sylvie L. Langlois (19725367) Barbara M. McGillivray (19725370) Steven J. M. Jones (9709382) Jan M. Friedman (11252261) Marco A. Marra (7610399) |
| author_role | author |
| dc.creator.none.fl_str_mv | Farah R. Zahir (18892108) Jill C. Mwenifumbo (19725358) Hye-Jung E. Chun (19725361) Emilia L. Lim (3348266) Clara D. M. Van Karnebeek (19725364) Madeline Couse (3385817) Karen L. Mungall (9709370) Leora Lee (3214851) Nancy Makela (4046018) Linlea Armstrong (4046036) Cornelius F. Boerkoel (12242496) Sylvie L. Langlois (19725367) Barbara M. McGillivray (19725370) Steven J. M. Jones (9709382) Jan M. Friedman (11252261) Marco A. Marra (7610399) |
| dc.date.none.fl_str_mv | 2017-05-24T03:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1186/s12864-017-3671-0 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/Comprehensive_whole_genome_sequence_analyses_yields_novel_genetic_and_structural_insights_for_Intellectual_Disability/27087994 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biological sciences Genetics Intellectual Disability Whole genome sequencing ARID1B PHF6 SPRY4 CACNB3 SQSTM1 UPF1 1q43 microdeletion Genome assembly |
| dc.title.none.fl_str_mv | Comprehensive whole genome sequence analyses yields novel genetic and structural insights for Intellectual Disability |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <h3>Background</h3><p dir="ltr">Intellectual Disability (ID) is among the most common global disorders, yet etiology is unknown in ~30% of patients despite clinical assessment. Whole genome sequencing (WGS) is able to interrogate the entire genome, providing potential to diagnose idiopathic patients.</p><h3>Methods</h3><p dir="ltr">We conducted WGS on eight children with idiopathic ID and brain structural defects, and their normal parents; carrying out an extensive data analyses, using standard and discovery approaches.</p><h3>Results</h3><p dir="ltr">We verified <i>de novo</i> pathogenic single nucleotide variants (SNV) in <i>ARID1B c.1595delG</i> and <i>PHF6 c.820C > T</i>, potentially causative <i>de novo</i> two base indels in <i>SQSTM1 c.115_116delinsTA</i> and <i>UPF1 c.1576_1577delinsA,</i> and <i>de novo</i> SNVs in <i>CACNB3 c.1289G > A,</i> and <i>SPRY4 c.508 T > A,</i> of uncertain significance. We report results from a large secondary control study of 2081 exomes probing the pathogenicity of the above genes. We analyzed structural variation by four different algorithms including <i>de novo</i> genome assembly. We confirmed a likely contributory 165 kb <i>de novo</i> heterozygous 1q43 microdeletion missed by clinical microarray. The <i>de novo</i> assembly resulted in unmasking hidden genome instability that was missed by standard re-alignment based algorithms. We also interrogated regulatory sequence variation for known and hypothesized ID genes and present useful strategies for WGS data analyses for non-coding variation.</p><h3>Conclusion</h3><p dir="ltr">This study provides an extensive analysis of WGS in the context of ID, providing genetic and structural insights into ID and yielding diagnoses.</p><h2>Other Information</h2><p dir="ltr">Published in: BMC Genomics<br>License: <a href="https://creativecommons.org/licenses/by/4.0/deed.en" rel="noreferrer noopener" target="_blank">https://creativecommons.org/licenses/by/4.0/</a> <br>See article on publisher's website: <a href="https://dx.doi.org/10.1186/s12864-017-3671-0" target="_blank">https://dx.doi.org/10.1186/s12864-017-3671-0</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_82c516d870477325da44af25ed33f9e3 |
| identifier_str_mv | 10.1186/s12864-017-3671-0 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/27087994 |
| publishDate | 2017 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | Comprehensive whole genome sequence analyses yields novel genetic and structural insights for Intellectual DisabilityFarah R. Zahir (18892108)Jill C. Mwenifumbo (19725358)Hye-Jung E. Chun (19725361)Emilia L. Lim (3348266)Clara D. M. Van Karnebeek (19725364)Madeline Couse (3385817)Karen L. Mungall (9709370)Leora Lee (3214851)Nancy Makela (4046018)Linlea Armstrong (4046036)Cornelius F. Boerkoel (12242496)Sylvie L. Langlois (19725367)Barbara M. McGillivray (19725370)Steven J. M. Jones (9709382)Jan M. Friedman (11252261)Marco A. Marra (7610399)Biological sciencesGeneticsIntellectual DisabilityWhole genome sequencingARID1BPHF6SPRY4CACNB3SQSTM1UPF11q43 microdeletionGenome assembly<h3>Background</h3><p dir="ltr">Intellectual Disability (ID) is among the most common global disorders, yet etiology is unknown in ~30% of patients despite clinical assessment. Whole genome sequencing (WGS) is able to interrogate the entire genome, providing potential to diagnose idiopathic patients.</p><h3>Methods</h3><p dir="ltr">We conducted WGS on eight children with idiopathic ID and brain structural defects, and their normal parents; carrying out an extensive data analyses, using standard and discovery approaches.</p><h3>Results</h3><p dir="ltr">We verified <i>de novo</i> pathogenic single nucleotide variants (SNV) in <i>ARID1B c.1595delG</i> and <i>PHF6 c.820C > T</i>, potentially causative <i>de novo</i> two base indels in <i>SQSTM1 c.115_116delinsTA</i> and <i>UPF1 c.1576_1577delinsA,</i> and <i>de novo</i> SNVs in <i>CACNB3 c.1289G > A,</i> and <i>SPRY4 c.508 T > A,</i> of uncertain significance. We report results from a large secondary control study of 2081 exomes probing the pathogenicity of the above genes. We analyzed structural variation by four different algorithms including <i>de novo</i> genome assembly. We confirmed a likely contributory 165 kb <i>de novo</i> heterozygous 1q43 microdeletion missed by clinical microarray. The <i>de novo</i> assembly resulted in unmasking hidden genome instability that was missed by standard re-alignment based algorithms. We also interrogated regulatory sequence variation for known and hypothesized ID genes and present useful strategies for WGS data analyses for non-coding variation.</p><h3>Conclusion</h3><p dir="ltr">This study provides an extensive analysis of WGS in the context of ID, providing genetic and structural insights into ID and yielding diagnoses.</p><h2>Other Information</h2><p dir="ltr">Published in: BMC Genomics<br>License: <a href="https://creativecommons.org/licenses/by/4.0/deed.en" rel="noreferrer noopener" target="_blank">https://creativecommons.org/licenses/by/4.0/</a> <br>See article on publisher's website: <a href="https://dx.doi.org/10.1186/s12864-017-3671-0" target="_blank">https://dx.doi.org/10.1186/s12864-017-3671-0</a></p>2017-05-24T03:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1186/s12864-017-3671-0https://figshare.com/articles/journal_contribution/Comprehensive_whole_genome_sequence_analyses_yields_novel_genetic_and_structural_insights_for_Intellectual_Disability/27087994CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/270879942017-05-24T03:00:00Z |
| spellingShingle | Comprehensive whole genome sequence analyses yields novel genetic and structural insights for Intellectual Disability Farah R. Zahir (18892108) Biological sciences Genetics Intellectual Disability Whole genome sequencing ARID1B PHF6 SPRY4 CACNB3 SQSTM1 UPF1 1q43 microdeletion Genome assembly |
| status_str | publishedVersion |
| title | Comprehensive whole genome sequence analyses yields novel genetic and structural insights for Intellectual Disability |
| title_full | Comprehensive whole genome sequence analyses yields novel genetic and structural insights for Intellectual Disability |
| title_fullStr | Comprehensive whole genome sequence analyses yields novel genetic and structural insights for Intellectual Disability |
| title_full_unstemmed | Comprehensive whole genome sequence analyses yields novel genetic and structural insights for Intellectual Disability |
| title_short | Comprehensive whole genome sequence analyses yields novel genetic and structural insights for Intellectual Disability |
| title_sort | Comprehensive whole genome sequence analyses yields novel genetic and structural insights for Intellectual Disability |
| topic | Biological sciences Genetics Intellectual Disability Whole genome sequencing ARID1B PHF6 SPRY4 CACNB3 SQSTM1 UPF1 1q43 microdeletion Genome assembly |