Comprehensive variant calling from whole‐genome sequencing identifies a complex inversion that disrupts ZFPM2 in familial congenital diaphragmatic hernia
Abstract Background Genetic disorders contribute to significant morbidity and mortality in critically ill newborns. Despite advances in genome sequencing technologies, a majority of neonatal cases remain unsolved. Complex structural variants (SVs) often elude conventional genome sequencing variant c...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2022-04-01
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| Series: | Molecular Genetics & Genomic Medicine |
| Online Access: | https://doi.org/10.1002/mgg3.1888 |
| _version_ | 1819060367657009152 |
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| author | Thomas J. Nicholas Najla Al‐Sweel Andrew Farrell Rong Mao Pinar Bayrak‐Toydemir Christine E. Miller Dawn Bentley Rachel Palmquist Barry Moore Edgar J. Hernandez Michael J. Cormier Eric Fredrickson Katherine Noble Shawn Rynearson Carson Holt Mary Anne Karren Joshua L. Bonkowsky Martin Tristani‐Firouzi Mark Yandell Gabor Marth Aaron R. Quinlan Luca Brunelli Reha M. Toydemir Brian J. Shayota John C. Carey Steven E. Boyden Sabrina Malone Jenkins |
| author_facet | Thomas J. Nicholas Najla Al‐Sweel Andrew Farrell Rong Mao Pinar Bayrak‐Toydemir Christine E. Miller Dawn Bentley Rachel Palmquist Barry Moore Edgar J. Hernandez Michael J. Cormier Eric Fredrickson Katherine Noble Shawn Rynearson Carson Holt Mary Anne Karren Joshua L. Bonkowsky Martin Tristani‐Firouzi Mark Yandell Gabor Marth Aaron R. Quinlan Luca Brunelli Reha M. Toydemir Brian J. Shayota John C. Carey Steven E. Boyden Sabrina Malone Jenkins |
| author_sort | Thomas J. Nicholas |
| collection | DOAJ |
| description | Abstract Background Genetic disorders contribute to significant morbidity and mortality in critically ill newborns. Despite advances in genome sequencing technologies, a majority of neonatal cases remain unsolved. Complex structural variants (SVs) often elude conventional genome sequencing variant calling pipelines and will explain a portion of these unsolved cases. Methods As part of the Utah NeoSeq project, we used a research‐based, rapid whole‐genome sequencing (WGS) protocol to investigate the genomic etiology for a newborn with a left‐sided congenital diaphragmatic hernia (CDH) and cardiac malformations, whose mother also had a history of CDH and atrial septal defect. Results Using both a novel, alignment‐free and traditional alignment‐based variant callers, we identified a maternally inherited complex SV on chromosome 8, consisting of an inversion flanked by deletions. This complex inversion, further confirmed using orthogonal molecular techniques, disrupts the ZFPM2 gene, which is associated with both CDH and various congenital heart defects. Conclusions Our results demonstrate that complex structural events, which often are unidentifiable or not reported by clinically validated testing procedures, can be discovered and accurately characterized with conventional, short‐read sequencing and underscore the utility of WGS as a first‐line diagnostic tool. |
| first_indexed | 2024-12-21T14:25:52Z |
| format | Article |
| id | doaj.art-1827760dc59544598719c7df6f5aa0f2 |
| institution | Directory Open Access Journal |
| issn | 2324-9269 |
| language | English |
| last_indexed | 2024-12-21T14:25:52Z |
| publishDate | 2022-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Genetics & Genomic Medicine |
| spelling | doaj.art-1827760dc59544598719c7df6f5aa0f22022-12-21T19:00:38ZengWileyMolecular Genetics & Genomic Medicine2324-92692022-04-01104n/an/a10.1002/mgg3.1888Comprehensive variant calling from whole‐genome sequencing identifies a complex inversion that disrupts ZFPM2 in familial congenital diaphragmatic herniaThomas J. Nicholas0Najla Al‐Sweel1Andrew Farrell2Rong Mao3Pinar Bayrak‐Toydemir4Christine E. Miller5Dawn Bentley6Rachel Palmquist7Barry Moore8Edgar J. Hernandez9Michael J. Cormier10Eric Fredrickson11Katherine Noble12Shawn Rynearson13Carson Holt14Mary Anne Karren15Joshua L. Bonkowsky16Martin Tristani‐Firouzi17Mark Yandell18Gabor Marth19Aaron R. Quinlan20Luca Brunelli21Reha M. Toydemir22Brian J. Shayota23John C. Carey24Steven E. Boyden25Sabrina Malone Jenkins26Department of Human Genetics, Utah Center for Genetic Discovery University of Utah Salt Lake City USAARUP Laboratories Salt Lake City USADepartment of Human Genetics, Utah Center for Genetic Discovery University of Utah Salt Lake City USAARUP Laboratories Salt Lake City USAARUP Laboratories Salt Lake City USAARUP Laboratories Salt Lake City USADivision of Neonatology, Department of Pediatrics University of Utah School of Medicine Salt Lake City USADivision of Pediatric Neurology, Department of Pediatrics University of Utah School of Medicine Salt Lake City USADepartment of Human Genetics, Utah Center for Genetic Discovery University of Utah Salt Lake City USADepartment of Human Genetics, Utah Center for Genetic Discovery University of Utah Salt Lake City USADepartment of Human Genetics, Utah Center for Genetic Discovery University of Utah Salt Lake City USAARUP Laboratories Salt Lake City USAARUP Laboratories Salt Lake City USADepartment of Human Genetics, Utah Center for Genetic Discovery University of Utah Salt Lake City USADepartment of Human Genetics, Utah Center for Genetic Discovery University of Utah Salt Lake City USADepartment of Human Genetics, Utah Center for Genetic Discovery University of Utah Salt Lake City USADivision of Pediatric Neurology, Department of Pediatrics University of Utah School of Medicine Salt Lake City USADivision of Pediatric Cardiology, Department of Pediatrics University of Utah School of Medicine Salt Lake City USADepartment of Human Genetics, Utah Center for Genetic Discovery University of Utah Salt Lake City USADepartment of Human Genetics, Utah Center for Genetic Discovery University of Utah Salt Lake City USADepartment of Human Genetics, Utah Center for Genetic Discovery University of Utah Salt Lake City USADivision of Neonatology, Department of Pediatrics University of Utah School of Medicine Salt Lake City USAARUP Laboratories Salt Lake City USADivision of Medical Genetics, Department of Pediatrics University of Utah School of Medicine Salt Lake City USADivision of Medical Genetics, Department of Pediatrics University of Utah School of Medicine Salt Lake City USADepartment of Human Genetics, Utah Center for Genetic Discovery University of Utah Salt Lake City USADivision of Neonatology, Department of Pediatrics University of Utah School of Medicine Salt Lake City USAAbstract Background Genetic disorders contribute to significant morbidity and mortality in critically ill newborns. Despite advances in genome sequencing technologies, a majority of neonatal cases remain unsolved. Complex structural variants (SVs) often elude conventional genome sequencing variant calling pipelines and will explain a portion of these unsolved cases. Methods As part of the Utah NeoSeq project, we used a research‐based, rapid whole‐genome sequencing (WGS) protocol to investigate the genomic etiology for a newborn with a left‐sided congenital diaphragmatic hernia (CDH) and cardiac malformations, whose mother also had a history of CDH and atrial septal defect. Results Using both a novel, alignment‐free and traditional alignment‐based variant callers, we identified a maternally inherited complex SV on chromosome 8, consisting of an inversion flanked by deletions. This complex inversion, further confirmed using orthogonal molecular techniques, disrupts the ZFPM2 gene, which is associated with both CDH and various congenital heart defects. Conclusions Our results demonstrate that complex structural events, which often are unidentifiable or not reported by clinically validated testing procedures, can be discovered and accurately characterized with conventional, short‐read sequencing and underscore the utility of WGS as a first‐line diagnostic tool.https://doi.org/10.1002/mgg3.1888 |
| spellingShingle | Thomas J. Nicholas Najla Al‐Sweel Andrew Farrell Rong Mao Pinar Bayrak‐Toydemir Christine E. Miller Dawn Bentley Rachel Palmquist Barry Moore Edgar J. Hernandez Michael J. Cormier Eric Fredrickson Katherine Noble Shawn Rynearson Carson Holt Mary Anne Karren Joshua L. Bonkowsky Martin Tristani‐Firouzi Mark Yandell Gabor Marth Aaron R. Quinlan Luca Brunelli Reha M. Toydemir Brian J. Shayota John C. Carey Steven E. Boyden Sabrina Malone Jenkins Comprehensive variant calling from whole‐genome sequencing identifies a complex inversion that disrupts ZFPM2 in familial congenital diaphragmatic hernia Molecular Genetics & Genomic Medicine |
| title | Comprehensive variant calling from whole‐genome sequencing identifies a complex inversion that disrupts ZFPM2 in familial congenital diaphragmatic hernia |
| title_full | Comprehensive variant calling from whole‐genome sequencing identifies a complex inversion that disrupts ZFPM2 in familial congenital diaphragmatic hernia |
| title_fullStr | Comprehensive variant calling from whole‐genome sequencing identifies a complex inversion that disrupts ZFPM2 in familial congenital diaphragmatic hernia |
| title_full_unstemmed | Comprehensive variant calling from whole‐genome sequencing identifies a complex inversion that disrupts ZFPM2 in familial congenital diaphragmatic hernia |
| title_short | Comprehensive variant calling from whole‐genome sequencing identifies a complex inversion that disrupts ZFPM2 in familial congenital diaphragmatic hernia |
| title_sort | comprehensive variant calling from whole genome sequencing identifies a complex inversion that disrupts zfpm2 in familial congenital diaphragmatic hernia |
| url | https://doi.org/10.1002/mgg3.1888 |
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