A Chromosome 7 Pericentric Inversion Defined at Single-Nucleotide Resolution Using Diagnostic Whole Genome Sequencing in a Patient with Hand-Foot-Genital Syndrome
Next generation sequencing methodologies are facilitating the rapid characterisation of novel structural variants at nucleotide resolution. These approaches are particularly applicable to variants initially identified using alternative molecular methods. We report a child born with bilateral postaxi...
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Published in | PloS one Vol. 11; no. 6; p. e0157075 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
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Public Library of Science
07.06.2016
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Abstract | Next generation sequencing methodologies are facilitating the rapid characterisation of novel structural variants at nucleotide resolution. These approaches are particularly applicable to variants initially identified using alternative molecular methods. We report a child born with bilateral postaxial syndactyly of the feet and bilateral fifth finger clinodactyly. This was presumed to be an autosomal recessive syndrome, due to the family history of consanguinity. Karyotype analysis revealed a homozygous pericentric inversion of chromosome 7 (46,XX,inv(7)(p15q21)x2) which was confirmed to be heterozygous in both unaffected parents. Since the resolution of the karyotype was insufficient to identify any putatively causative gene, we undertook medium-coverage whole genome sequencing using paired-end reads, in order to elucidate the molecular breakpoints. In a two-step analysis, we first narrowed down the region by identifying discordant read-pairs, and then determined the precise molecular breakpoint by analysing the mapping locations of "soft-clipped" breakpoint-spanning reads. PCR and Sanger sequencing confirmed the identified breakpoints, both of which were located in intergenic regions. Significantly, the 7p15 breakpoint was located 523 kb upstream of HOXA13, the locus for hand-foot-genital syndrome. By inference from studies of HOXA locus control in the mouse, we suggest that the inversion has delocalised a HOXA13 enhancer to produce the phenotype observed in our patient. This study demonstrates how modern genetic diagnostic approach can characterise structural variants at nucleotide resolution and provide potential insights into functional regulation. |
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AbstractList | Next generation sequencing methodologies are facilitating the rapid characterisation of novel structural variants at nucleotide resolution. These approaches are particularly applicable to variants initially identified using alternative molecular methods. We report a child born with bilateral postaxial syndactyly of the feet and bilateral fifth finger clinodactyly. This was presumed to be an autosomal recessive syndrome, due to the family history of consanguinity. Karyotype analysis revealed a homozygous pericentric inversion of chromosome 7 (46,XX,inv(7)(p15q21)x2) which was confirmed to be heterozygous in both unaffected parents. Since the resolution of the karyotype was insufficient to identify any putatively causative gene, we undertook medium-coverage whole genome sequencing using paired-end reads, in order to elucidate the molecular breakpoints. In a two-step analysis, we first narrowed down the region by identifying discordant read-pairs, and then determined the precise molecular breakpoint by analysing the mapping locations of "soft-clipped" breakpoint-spanning reads. PCR and Sanger sequencing confirmed the identified breakpoints, both of which were located in intergenic regions. Significantly, the 7p15 breakpoint was located 523 kb upstream of HOXA13, the locus for hand-foot-genital syndrome. By inference from studies of HOXA locus control in the mouse, we suggest that the inversion has delocalised a HOXA13 enhancer to produce the phenotype observed in our patient. This study demonstrates how modern genetic diagnostic approach can characterise structural variants at nucleotide resolution and provide potential insights into functional regulation. Next generation sequencing methodologies are facilitating the rapid characterisation of novel structural variants at nucleotide resolution. These approaches are particularly applicable to variants initially identified using alternative molecular methods. We report a child born with bilateral postaxial syndactyly of the feet and bilateral fifth finger clinodactyly. This was presumed to be an autosomal recessive syndrome, due to the family history of consanguinity. Karyotype analysis revealed a homozygous pericentric inversion of chromosome 7 (46,XX,inv(7)(p15q21)x2) which was confirmed to be heterozygous in both unaffected parents. Since the resolution of the karyotype was insufficient to identify any putatively causative gene, we undertook medium-coverage whole genome sequencing using paired-end reads, in order to elucidate the molecular breakpoints. In a two-step analysis, we first narrowed down the region by identifying discordant read-pairs, and then determined the precise molecular breakpoint by analysing the mapping locations of “soft-clipped” breakpoint-spanning reads. PCR and Sanger sequencing confirmed the identified breakpoints, both of which were located in intergenic regions. Significantly, the 7p15 breakpoint was located 523 kb upstream of HOXA13 , the locus for hand-foot-genital syndrome. By inference from studies of HOXA locus control in the mouse, we suggest that the inversion has delocalised a HOXA13 enhancer to produce the phenotype observed in our patient. This study demonstrates how modern genetic diagnostic approach can characterise structural variants at nucleotide resolution and provide potential insights into functional regulation. |
Audience | Academic |
Author | Harrison, Sally M Lascelles, Carolina Watson, Christopher M Sheridan, Eamonn Crinnion, Laura A Carr, Ian M Bonthron, David T Antanaviciute, Agne |
AuthorAffiliation | 2 School of Medicine, University of Leeds, St. James’s University Hospital, Leeds, LS9 7TF, United Kingdom Virginia Tech, UNITED STATES 1 Yorkshire Regional Genetics Service, St. James’s University Hospital, Leeds, LS9 7TF, United Kingdom |
AuthorAffiliation_xml | – name: 1 Yorkshire Regional Genetics Service, St. James’s University Hospital, Leeds, LS9 7TF, United Kingdom – name: 2 School of Medicine, University of Leeds, St. James’s University Hospital, Leeds, LS9 7TF, United Kingdom – name: Virginia Tech, UNITED STATES |
Author_xml | – sequence: 1 givenname: Christopher M orcidid: 0000-0003-2371-1844 surname: Watson fullname: Watson, Christopher M organization: School of Medicine, University of Leeds, St. James's University Hospital, Leeds, LS9 7TF, United Kingdom – sequence: 2 givenname: Laura A surname: Crinnion fullname: Crinnion, Laura A organization: School of Medicine, University of Leeds, St. James's University Hospital, Leeds, LS9 7TF, United Kingdom – sequence: 3 givenname: Sally M surname: Harrison fullname: Harrison, Sally M organization: School of Medicine, University of Leeds, St. James's University Hospital, Leeds, LS9 7TF, United Kingdom – sequence: 4 givenname: Carolina surname: Lascelles fullname: Lascelles, Carolina organization: School of Medicine, University of Leeds, St. James's University Hospital, Leeds, LS9 7TF, United Kingdom – sequence: 5 givenname: Agne surname: Antanaviciute fullname: Antanaviciute, Agne organization: School of Medicine, University of Leeds, St. James's University Hospital, Leeds, LS9 7TF, United Kingdom – sequence: 6 givenname: Ian M surname: Carr fullname: Carr, Ian M organization: School of Medicine, University of Leeds, St. James's University Hospital, Leeds, LS9 7TF, United Kingdom – sequence: 7 givenname: David T surname: Bonthron fullname: Bonthron, David T organization: School of Medicine, University of Leeds, St. James's University Hospital, Leeds, LS9 7TF, United Kingdom – sequence: 8 givenname: Eamonn surname: Sheridan fullname: Sheridan, Eamonn organization: School of Medicine, University of Leeds, St. James's University Hospital, Leeds, LS9 7TF, United Kingdom |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/27272187$$D View this record in MEDLINE/PubMed |
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CitedBy_id | crossref_primary_10_1186_s13039_017_0345_1 crossref_primary_10_1186_s13039_023_00638_0 crossref_primary_10_1016_j_ajhg_2024_04_018 crossref_primary_10_1002_humu_24106 crossref_primary_10_1136_jmg_2022_108753 |
Cites_doi | 10.1038/ng0297-179 10.1002/ajmg.a.33860 10.1002/humu.22490 10.1093/bioinformatics/btp352 10.1038/ng0796-284 10.1086/302452 10.1101/gr.229202 10.1371/journal.pgen.1004018 10.1002/humu.21216 10.1016/j.ajhg.2009.03.010 10.1016/j.ygeno.2013.04.006 10.1093/bib/bbs017 10.1111/j.1525-142X.2008.00253.x 10.1093/hmg/ddh306 10.1002/dvdy.22183 10.1016/j.cell.2011.10.023 10.1002/ajmg.a.36679 10.1111/j.1525-142X.2004.04050.x 10.1093/bioinformatics/btp324 10.14806/ej.17.1.200 10.1002/ajmg.10776 10.1086/302961 |
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Copyright | COPYRIGHT 2016 Public Library of Science 2016 Watson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. 2016 Watson et al 2016 Watson et al |
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Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Competing Interests: The authors have declared that no competing interests exist. Conceived and designed the experiments: CMW IMC DTB ES. Performed the experiments: LAC SMH CL AA. Analyzed the data: CMW DTB ES. Wrote the paper: CMW DTB ES. |
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SubjectTerms | Abnormalities, Multiple - genetics Bioinformatics Biology and Life Sciences Breakpoints Chromosome 7 Chromosome Breakpoints Chromosome Inversion Chromosomes, Human, Pair 7 - genetics Consanguinity Diagnostic systems DNA sequencing Feet Female Foot Deformities, Congenital - genetics Gene expression Gene mapping Gene sequencing Genetic aspects Genetic engineering Genetics Genomes Genomics Hand Deformities, Congenital - genetics High-Throughput Nucleotide Sequencing Homeodomain Proteins - genetics Humans Identification methods Infant, Newborn Inversion Karyotypes Laboratories Loci Medical diagnosis Medicine Mutation Palmar-plantar erythrodysesthesia Parents Patient outcomes Research and Analysis Methods Risk factors Sequence Analysis, DNA Syndactyly Urogenital Abnormalities - genetics |
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Title | A Chromosome 7 Pericentric Inversion Defined at Single-Nucleotide Resolution Using Diagnostic Whole Genome Sequencing in a Patient with Hand-Foot-Genital Syndrome |
URI | https://www.ncbi.nlm.nih.gov/pubmed/27272187 https://www.proquest.com/docview/1794495380 https://search.proquest.com/docview/1808726704 https://pubmed.ncbi.nlm.nih.gov/PMC4896502 https://doaj.org/article/824d612fa70a4520b39526d2fa623574 http://dx.doi.org/10.1371/journal.pone.0157075 |
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