Genetic analysis of 20 patients with hypomyelinating leukodystrophy by trio-based whole-exome sequencing
Hypomyelinating leukodystrophies (HLDs) are a rare group of disorders characterized by myelin deficit of the brain-based on MRI. Here, we studied 20 patients with unexplained HLD to uncover their genetic etiology through whole-exome sequencing (WES). Trio-based WES was performed for 20 unresolved HL...
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| Veröffentlicht in: | Journal of human genetics 2021-08, Vol.66 (8), p.761-768 |
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| creator | Yan, Huifang Ji, Haoran Kubisiak, Thomas Wu, Ye Xiao, Jiangxi Gu, Qiang Yang, Yanling Xie, Han Ji, Taoyun Gao, Kai Li, Dongxiao Xiong, Hui Shi, Zhen Li, Ming Zhang, Yuehua Duan, Ruoyu Bao, Xinhua Jiang, Yuwu Burmeister, Margit Wang, Jingmin |
| description | Hypomyelinating leukodystrophies (HLDs) are a rare group of disorders characterized by myelin deficit of the brain-based on MRI. Here, we studied 20 patients with unexplained HLD to uncover their genetic etiology through whole-exome sequencing (WES). Trio-based WES was performed for 20 unresolved HLDs families after genetic tests for the PLP1 duplication and a panel of 115 known leukodystrophy-related genes. Variants in both known genes that related to HLDs and promising candidate genes were analyzed. Minigene splicing assay was conducted to confirm the effect of splice region variant. All 20 patients were diagnosed with HLDs clinically based on myelin deficit on MRI and impaired motor ability. Through WES, in 11 of 20 trios, 15 causative variants were detected in seven genes TUBB4A, POLR1C, POLR3A, SOX10, TMEM106B, DEGS1, and TMEM63A. The last three genes have just been discovered. Of 15 variants, six were novel. Using minigene splicing assay, splice variant POLR3A c.1770 + 5 G > C was proved to disrupt the normal splicing of intron 13 and led to a premature stop codon at position 618 (p.(P591Vfs*28)). Our analysis determined the molecular diagnosis of 11 HLDs patients. It emphasizes the heterogenicity of HLDs, the diagnostic power of trio-based WES for HLDs. Comprehensive analysis including a focus on candidate genes helps to discover novel disease-causing genes, determine the diagnosis for the first time, and improve the yield of WES. Moreover, novel mutations identified in TUBB4A, POLR3A, and POLR1C expand the mutation spectrum of these genes. |
| doi_str_mv | 10.1038/s10038-020-00896-5 |
| format | Article |
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Here, we studied 20 patients with unexplained HLD to uncover their genetic etiology through whole-exome sequencing (WES). Trio-based WES was performed for 20 unresolved HLDs families after genetic tests for the PLP1 duplication and a panel of 115 known leukodystrophy-related genes. Variants in both known genes that related to HLDs and promising candidate genes were analyzed. Minigene splicing assay was conducted to confirm the effect of splice region variant. All 20 patients were diagnosed with HLDs clinically based on myelin deficit on MRI and impaired motor ability. Through WES, in 11 of 20 trios, 15 causative variants were detected in seven genes TUBB4A, POLR1C, POLR3A, SOX10, TMEM106B, DEGS1, and TMEM63A. The last three genes have just been discovered. Of 15 variants, six were novel. Using minigene splicing assay, splice variant POLR3A c.1770 + 5 G > C was proved to disrupt the normal splicing of intron 13 and led to a premature stop codon at position 618 (p.(P591Vfs*28)). Our analysis determined the molecular diagnosis of 11 HLDs patients. It emphasizes the heterogenicity of HLDs, the diagnostic power of trio-based WES for HLDs. Comprehensive analysis including a focus on candidate genes helps to discover novel disease-causing genes, determine the diagnosis for the first time, and improve the yield of WES. Moreover, novel mutations identified in TUBB4A, POLR3A, and POLR1C expand the mutation spectrum of these genes.</description><identifier>ISSN: 1434-5161</identifier><identifier>EISSN: 1435-232X</identifier><identifier>DOI: 10.1038/s10038-020-00896-5</identifier><identifier>PMID: 33597727</identifier><language>eng</language><publisher>England: Nature Publishing Group</publisher><subject>Alternative splicing ; Diagnosis ; Etiology ; Genetic analysis ; Genetic screening ; Leukodystrophy ; Magnetic resonance imaging ; Mutation ; Myelin ; Myelin proteolipid protein ; Nonsense mutation ; Sox10 protein ; Splicing ; Stop codon</subject><ispartof>Journal of human genetics, 2021-08, Vol.66 (8), p.761-768</ispartof><rights>The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>The Author(s) 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c454t-a4a298261ab1dc148a9f49e1e6b83e8b64054be22e09ea44759a445d4d79611e3</citedby><cites>FETCH-LOGICAL-c454t-a4a298261ab1dc148a9f49e1e6b83e8b64054be22e09ea44759a445d4d79611e3</cites><orcidid>0000-0003-4138-2992 ; 0000-0001-7297-9228</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33597727$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yan, Huifang</creatorcontrib><creatorcontrib>Ji, Haoran</creatorcontrib><creatorcontrib>Kubisiak, Thomas</creatorcontrib><creatorcontrib>Wu, Ye</creatorcontrib><creatorcontrib>Xiao, Jiangxi</creatorcontrib><creatorcontrib>Gu, Qiang</creatorcontrib><creatorcontrib>Yang, Yanling</creatorcontrib><creatorcontrib>Xie, Han</creatorcontrib><creatorcontrib>Ji, Taoyun</creatorcontrib><creatorcontrib>Gao, Kai</creatorcontrib><creatorcontrib>Li, Dongxiao</creatorcontrib><creatorcontrib>Xiong, Hui</creatorcontrib><creatorcontrib>Shi, Zhen</creatorcontrib><creatorcontrib>Li, Ming</creatorcontrib><creatorcontrib>Zhang, Yuehua</creatorcontrib><creatorcontrib>Duan, Ruoyu</creatorcontrib><creatorcontrib>Bao, Xinhua</creatorcontrib><creatorcontrib>Jiang, Yuwu</creatorcontrib><creatorcontrib>Burmeister, Margit</creatorcontrib><creatorcontrib>Wang, Jingmin</creatorcontrib><title>Genetic analysis of 20 patients with hypomyelinating leukodystrophy by trio-based whole-exome sequencing</title><title>Journal of human genetics</title><addtitle>J Hum Genet</addtitle><description>Hypomyelinating leukodystrophies (HLDs) are a rare group of disorders characterized by myelin deficit of the brain-based on MRI. Here, we studied 20 patients with unexplained HLD to uncover their genetic etiology through whole-exome sequencing (WES). Trio-based WES was performed for 20 unresolved HLDs families after genetic tests for the PLP1 duplication and a panel of 115 known leukodystrophy-related genes. Variants in both known genes that related to HLDs and promising candidate genes were analyzed. Minigene splicing assay was conducted to confirm the effect of splice region variant. All 20 patients were diagnosed with HLDs clinically based on myelin deficit on MRI and impaired motor ability. Through WES, in 11 of 20 trios, 15 causative variants were detected in seven genes TUBB4A, POLR1C, POLR3A, SOX10, TMEM106B, DEGS1, and TMEM63A. The last three genes have just been discovered. Of 15 variants, six were novel. Using minigene splicing assay, splice variant POLR3A c.1770 + 5 G > C was proved to disrupt the normal splicing of intron 13 and led to a premature stop codon at position 618 (p.(P591Vfs*28)). Our analysis determined the molecular diagnosis of 11 HLDs patients. It emphasizes the heterogenicity of HLDs, the diagnostic power of trio-based WES for HLDs. Comprehensive analysis including a focus on candidate genes helps to discover novel disease-causing genes, determine the diagnosis for the first time, and improve the yield of WES. Moreover, novel mutations identified in TUBB4A, POLR3A, and POLR1C expand the mutation spectrum of these genes.</description><subject>Alternative splicing</subject><subject>Diagnosis</subject><subject>Etiology</subject><subject>Genetic analysis</subject><subject>Genetic screening</subject><subject>Leukodystrophy</subject><subject>Magnetic resonance imaging</subject><subject>Mutation</subject><subject>Myelin</subject><subject>Myelin proteolipid protein</subject><subject>Nonsense mutation</subject><subject>Sox10 protein</subject><subject>Splicing</subject><subject>Stop 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Genet</addtitle><date>2021-08-01</date><risdate>2021</risdate><volume>66</volume><issue>8</issue><spage>761</spage><epage>768</epage><pages>761-768</pages><issn>1434-5161</issn><eissn>1435-232X</eissn><abstract>Hypomyelinating leukodystrophies (HLDs) are a rare group of disorders characterized by myelin deficit of the brain-based on MRI. 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Our analysis determined the molecular diagnosis of 11 HLDs patients. It emphasizes the heterogenicity of HLDs, the diagnostic power of trio-based WES for HLDs. Comprehensive analysis including a focus on candidate genes helps to discover novel disease-causing genes, determine the diagnosis for the first time, and improve the yield of WES. Moreover, novel mutations identified in TUBB4A, POLR3A, and POLR1C expand the mutation spectrum of these genes.</abstract><cop>England</cop><pub>Nature Publishing Group</pub><pmid>33597727</pmid><doi>10.1038/s10038-020-00896-5</doi><tpages>8</tpages><orcidid>https://orcid.org/0000-0003-4138-2992</orcidid><orcidid>https://orcid.org/0000-0001-7297-9228</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Journal of human genetics, 2021-08, Vol.66 (8), p.761-768 |
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| source | Alma/SFX Local Collection |
| subjects | Alternative splicing Diagnosis Etiology Genetic analysis Genetic screening Leukodystrophy Magnetic resonance imaging Mutation Myelin Myelin proteolipid protein Nonsense mutation Sox10 protein Splicing Stop codon |
| title | Genetic analysis of 20 patients with hypomyelinating leukodystrophy by trio-based whole-exome sequencing |
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