Detection of inversion with breakpoints in ARSB causing MPS VI by whole-genome sequencing: lessons learned and best practices
IntroductionMucopolysaccharidosis type VI (MPSVI), an autosomal recessive lysosomal storage disorder caused by pathogenic variants in ARSB gene. Usually, whole exome sequencing (WES) can identify these variants, and if WES failed to detect causative variants, whole-genome sequencing (WGS) may be con...
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Frontiers Media S.A.
2025-01-01
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| author | Yufeng Huang Wenyue Deng Hui Huang Xiankai Zhang Xiaohong Chen Jian Ye Sukun Luo Ting Yu Hui Yao Hao Du Xuelian He |
| author_facet | Yufeng Huang Wenyue Deng Hui Huang Xiankai Zhang Xiaohong Chen Jian Ye Sukun Luo Ting Yu Hui Yao Hao Du Xuelian He |
| author_sort | Yufeng Huang |
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| description | IntroductionMucopolysaccharidosis type VI (MPSVI), an autosomal recessive lysosomal storage disorder caused by pathogenic variants in ARSB gene. Usually, whole exome sequencing (WES) can identify these variants, and if WES failed to detect causative variants, whole-genome sequencing (WGS) may be considered to investigate deep intronic variations and structural alterations in patients.MethodsWhole-exome sequencing (WES) and whole genome sequencing (WGS) were performed in a Chinese family having a boy with suspected diagnosis of MPS with macrocephaly, coarse facial features, broad forehead, thick lips, frontal bossing, craniosynostosis, blue spots, frequent upper respiratory infections, inguinal hernia, and dysostosis multiplex. Lysosomal enzymatic assays for leucocytes were used to assess the activity of arylsulfatase B of the boy’s leucocytes. Sanger sequencing and karyotyping analysis were used to validate the variants identified in the boy and his parents.ResultsThis boy diagnosed with MPSVI based on clinical phenotypes and laboratory biochemical assays, and WES identified only a maternally inherited missense variant, c.908G>T (p.Gly303Val), in the ARSB gene. By performing WGS, we found a paracentric inversion involving chromosome 5q14.1q13.2 (78180730-138771424 inv), disrupting the ARSB gene on the proband and his father. The inversion was confirmed through karyotyping analysis, and the breakpoints were validated by agarose gel electrophoresis and Sanger sequencing.DisscussionThis study reminds us that WGS should be done when WES failed to achieve a molecular diagonosis, and it also underscores the importance of WGS especially in cases of high clinical suspicion. |
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| institution | Kabale University |
| issn | 1664-8021 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Genetics |
| spelling | doaj-art-8e3672e469704594899098c52ed5bc182025-01-08T06:11:49ZengFrontiers Media S.A.Frontiers in Genetics1664-80212025-01-011510.3389/fgene.2024.14524981452498Detection of inversion with breakpoints in ARSB causing MPS VI by whole-genome sequencing: lessons learned and best practicesYufeng Huang0Wenyue Deng1Hui Huang2Xiankai Zhang3Xiaohong Chen4Jian Ye5Sukun Luo6Ting Yu7Hui Yao8Hao Du9Xuelian He10Genetics and Precision Medical Center, Wuhan Children’s Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Neurosurgery, Wuhan Children’s Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaGenetics and Precision Medical Center, Wuhan Children’s Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaGenetics and Precision Medical Center, Wuhan Children’s Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Endocrinology and Genetic Metabolism, Wuhan Children’s Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaGenetics and Precision Medical Center, Wuhan Children’s Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaGenetics and Precision Medical Center, Wuhan Children’s Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaGenetics and Precision Medical Center, Wuhan Children’s Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Endocrinology and Genetic Metabolism, Wuhan Children’s Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Neurosurgery, Wuhan Children’s Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaGenetics and Precision Medical Center, Wuhan Children’s Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaIntroductionMucopolysaccharidosis type VI (MPSVI), an autosomal recessive lysosomal storage disorder caused by pathogenic variants in ARSB gene. Usually, whole exome sequencing (WES) can identify these variants, and if WES failed to detect causative variants, whole-genome sequencing (WGS) may be considered to investigate deep intronic variations and structural alterations in patients.MethodsWhole-exome sequencing (WES) and whole genome sequencing (WGS) were performed in a Chinese family having a boy with suspected diagnosis of MPS with macrocephaly, coarse facial features, broad forehead, thick lips, frontal bossing, craniosynostosis, blue spots, frequent upper respiratory infections, inguinal hernia, and dysostosis multiplex. Lysosomal enzymatic assays for leucocytes were used to assess the activity of arylsulfatase B of the boy’s leucocytes. Sanger sequencing and karyotyping analysis were used to validate the variants identified in the boy and his parents.ResultsThis boy diagnosed with MPSVI based on clinical phenotypes and laboratory biochemical assays, and WES identified only a maternally inherited missense variant, c.908G>T (p.Gly303Val), in the ARSB gene. By performing WGS, we found a paracentric inversion involving chromosome 5q14.1q13.2 (78180730-138771424 inv), disrupting the ARSB gene on the proband and his father. The inversion was confirmed through karyotyping analysis, and the breakpoints were validated by agarose gel electrophoresis and Sanger sequencing.DisscussionThis study reminds us that WGS should be done when WES failed to achieve a molecular diagonosis, and it also underscores the importance of WGS especially in cases of high clinical suspicion.https://www.frontiersin.org/articles/10.3389/fgene.2024.1452498/fullmucopolysaccharidosis type VIwhole-genome sequencingARSBinversionbreakpoint |
| spellingShingle | Yufeng Huang Wenyue Deng Hui Huang Xiankai Zhang Xiaohong Chen Jian Ye Sukun Luo Ting Yu Hui Yao Hao Du Xuelian He Detection of inversion with breakpoints in ARSB causing MPS VI by whole-genome sequencing: lessons learned and best practices Frontiers in Genetics mucopolysaccharidosis type VI whole-genome sequencing ARSB inversion breakpoint |
| title | Detection of inversion with breakpoints in ARSB causing MPS VI by whole-genome sequencing: lessons learned and best practices |
| title_full | Detection of inversion with breakpoints in ARSB causing MPS VI by whole-genome sequencing: lessons learned and best practices |
| title_fullStr | Detection of inversion with breakpoints in ARSB causing MPS VI by whole-genome sequencing: lessons learned and best practices |
| title_full_unstemmed | Detection of inversion with breakpoints in ARSB causing MPS VI by whole-genome sequencing: lessons learned and best practices |
| title_short | Detection of inversion with breakpoints in ARSB causing MPS VI by whole-genome sequencing: lessons learned and best practices |
| title_sort | detection of inversion with breakpoints in arsb causing mps vi by whole genome sequencing lessons learned and best practices |
| topic | mucopolysaccharidosis type VI whole-genome sequencing ARSB inversion breakpoint |
| url | https://www.frontiersin.org/articles/10.3389/fgene.2024.1452498/full |
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