Identification of Novel Risk Variants of Non-Syndromic Cleft Palate by Targeted Gene Panel Sequencing
Non-syndromic cleft palate (ns-CP) has a genetically heterogeneous aetiology. Numerous studies have suggested a crucial role of rare coding variants in characterizing the unrevealed component of genetic variation in ns-CP called the “missing heritability”. Therefore, this study aimed to detect low-f...
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MDPI AG
2023-03-01
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| Series: | Journal of Clinical Medicine |
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| Online Access: | https://www.mdpi.com/2077-0383/12/5/2051 |
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| author | Justyna Dąbrowska Barbara Biedziak Agnieszka Bogdanowicz Adrianna Mostowska |
| author_facet | Justyna Dąbrowska Barbara Biedziak Agnieszka Bogdanowicz Adrianna Mostowska |
| author_sort | Justyna Dąbrowska |
| collection | DOAJ |
| description | Non-syndromic cleft palate (ns-CP) has a genetically heterogeneous aetiology. Numerous studies have suggested a crucial role of rare coding variants in characterizing the unrevealed component of genetic variation in ns-CP called the “missing heritability”. Therefore, this study aimed to detect low-frequency variants that are implicated in ns-CP aetiology in the Polish population. For this purpose, coding regions of 423 genes associated with orofacial cleft anomalies and/or involved with facial development were screened in 38 ns-CP patients using the next-generation sequencing technology. After multistage selection and prioritisation, eight novel and four known rare variants that may influence an individual’s risk of ns-CP were identified. Among detected alternations, seven were located in novel candidate genes for ns-CP, including <i>COL17A1 (</i>c.2435-1G>A), <i>DLG1</i> (c.1586G>C, p.Glu562Asp), <i>NHS (</i>c.568G>C, p.Val190Leu—de novo variant), <i>NOTCH2</i> (c.1997A>G, p.Tyr666Cys), <i>TBX18</i> (c.647A>T, p.His225Leu), <i>VAX1</i> (c.400G>A, p.Ala134Thr) and <i>WNT5B</i> (c.716G>T, p.Arg239Leu). The remaining risk variants were identified within genes previously linked to ns-CP, confirming their contribution to this anomaly. This list included <i>ARHGAP29</i> (c.1706G>A, p.Arg569Gln), <i>FLNB</i> (c.3605A>G, Tyr1202Cys), <i>IRF6</i> (224A>G, p.Asp75Gly—de novo variant), <i>LRP6</i> (c.481C>A, p.Pro161Thr) and <i>TP63</i> (c.353A>T, p.Asn118Ile). In summary, this study provides further insights into the genetic components contributing to ns-CP aetiology and identifies novel susceptibility genes for this craniofacial anomaly. |
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| format | Article |
| id | doaj.art-88dfb6804e4a41d59bbc2b16768c3b12 |
| institution | Directory Open Access Journal |
| issn | 2077-0383 |
| language | English |
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| spelling | doaj.art-88dfb6804e4a41d59bbc2b16768c3b122023-11-17T08:01:58ZengMDPI AGJournal of Clinical Medicine2077-03832023-03-01125205110.3390/jcm12052051Identification of Novel Risk Variants of Non-Syndromic Cleft Palate by Targeted Gene Panel SequencingJustyna Dąbrowska0Barbara Biedziak1Agnieszka Bogdanowicz2Adrianna Mostowska3Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, 6 Swiecickiego Street, 60-781 Poznan, PolandDepartment of Orthodontics and Craniofacial Anomalies, Poznan University of Medical Sciences, 60-812 Poznan, PolandDepartment of Orthodontics and Craniofacial Anomalies, Poznan University of Medical Sciences, 60-812 Poznan, PolandDepartment of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, 6 Swiecickiego Street, 60-781 Poznan, PolandNon-syndromic cleft palate (ns-CP) has a genetically heterogeneous aetiology. Numerous studies have suggested a crucial role of rare coding variants in characterizing the unrevealed component of genetic variation in ns-CP called the “missing heritability”. Therefore, this study aimed to detect low-frequency variants that are implicated in ns-CP aetiology in the Polish population. For this purpose, coding regions of 423 genes associated with orofacial cleft anomalies and/or involved with facial development were screened in 38 ns-CP patients using the next-generation sequencing technology. After multistage selection and prioritisation, eight novel and four known rare variants that may influence an individual’s risk of ns-CP were identified. Among detected alternations, seven were located in novel candidate genes for ns-CP, including <i>COL17A1 (</i>c.2435-1G>A), <i>DLG1</i> (c.1586G>C, p.Glu562Asp), <i>NHS (</i>c.568G>C, p.Val190Leu—de novo variant), <i>NOTCH2</i> (c.1997A>G, p.Tyr666Cys), <i>TBX18</i> (c.647A>T, p.His225Leu), <i>VAX1</i> (c.400G>A, p.Ala134Thr) and <i>WNT5B</i> (c.716G>T, p.Arg239Leu). The remaining risk variants were identified within genes previously linked to ns-CP, confirming their contribution to this anomaly. This list included <i>ARHGAP29</i> (c.1706G>A, p.Arg569Gln), <i>FLNB</i> (c.3605A>G, Tyr1202Cys), <i>IRF6</i> (224A>G, p.Asp75Gly—de novo variant), <i>LRP6</i> (c.481C>A, p.Pro161Thr) and <i>TP63</i> (c.353A>T, p.Asn118Ile). In summary, this study provides further insights into the genetic components contributing to ns-CP aetiology and identifies novel susceptibility genes for this craniofacial anomaly.https://www.mdpi.com/2077-0383/12/5/2051non-syndromic cleft palaterare coding variantspathogenic variantsNGS gene panel |
| spellingShingle | Justyna Dąbrowska Barbara Biedziak Agnieszka Bogdanowicz Adrianna Mostowska Identification of Novel Risk Variants of Non-Syndromic Cleft Palate by Targeted Gene Panel Sequencing Journal of Clinical Medicine non-syndromic cleft palate rare coding variants pathogenic variants NGS gene panel |
| title | Identification of Novel Risk Variants of Non-Syndromic Cleft Palate by Targeted Gene Panel Sequencing |
| title_full | Identification of Novel Risk Variants of Non-Syndromic Cleft Palate by Targeted Gene Panel Sequencing |
| title_fullStr | Identification of Novel Risk Variants of Non-Syndromic Cleft Palate by Targeted Gene Panel Sequencing |
| title_full_unstemmed | Identification of Novel Risk Variants of Non-Syndromic Cleft Palate by Targeted Gene Panel Sequencing |
| title_short | Identification of Novel Risk Variants of Non-Syndromic Cleft Palate by Targeted Gene Panel Sequencing |
| title_sort | identification of novel risk variants of non syndromic cleft palate by targeted gene panel sequencing |
| topic | non-syndromic cleft palate rare coding variants pathogenic variants NGS gene panel |
| url | https://www.mdpi.com/2077-0383/12/5/2051 |
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