Early onset horizontal gaze palsy and progressive scoliosis due to a noncanonical splicing‐site variant and a missense variant in the ROBO3 gene
Abstract Background Homozygous or compound heterozygous ROBO3 gene mutations cause horizontal gaze palsy with progressive scoliosis (HGPPS). This is an autosomal recessive disorder that is characterized by congenital absence or severe restriction of horizontal gaze and progressive scoliosis. To date...
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| Format: | Article |
| Language: | English |
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Wiley
2023-09-01
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| Series: | Molecular Genetics & Genomic Medicine |
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| Online Access: | https://doi.org/10.1002/mgg3.2215 |
| _version_ | 1827820503661805568 |
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| author | Sheng Yi Zailong Qin Xunzhao Zhou Junjie Chen Shang Yi Qiuli Chen Limei Huang Qinle Zhang Biyan Chen Jingsi Luo |
| author_facet | Sheng Yi Zailong Qin Xunzhao Zhou Junjie Chen Shang Yi Qiuli Chen Limei Huang Qinle Zhang Biyan Chen Jingsi Luo |
| author_sort | Sheng Yi |
| collection | DOAJ |
| description | Abstract Background Homozygous or compound heterozygous ROBO3 gene mutations cause horizontal gaze palsy with progressive scoliosis (HGPPS). This is an autosomal recessive disorder that is characterized by congenital absence or severe restriction of horizontal gaze and progressive scoliosis. To date, almost 100 patients with HGPPS have been reported and 55 ROBO3 mutations have been identified. Methods We described an HGPPS patient and performed whole‐exome sequencing (WES) to identify the causative gene. Results We identified a missense variant and a splice‐site variant in the ROBO3 gene in the proband. Sanger sequencing of cDNA revealed the presence of an aberrant transcript with retention of 700 bp from intron 17, which was caused by a variation in the noncanonical splicing site. We identified five additional ROBO3 variants, which were likely pathogenic, and estimated the overall allele frequency in the southern Chinese population to be 9.44 × 10−4, by a review of our in‐house database. Conclusion This study has broadened the mutation spectrum of the ROBO3 gene and has expanded our knowledge of variants in noncanonical splicing sites. The results could help to provide more accurate genetic counseling to affected families and prospective couples. We suggest that the ROBO3 gene should be included in the local screening strategy. |
| first_indexed | 2024-03-12T01:28:47Z |
| format | Article |
| id | doaj.art-e38971df665f4890b1bf7887add53696 |
| institution | Directory Open Access Journal |
| issn | 2324-9269 |
| language | English |
| last_indexed | 2024-03-12T01:28:47Z |
| publishDate | 2023-09-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Genetics & Genomic Medicine |
| spelling | doaj.art-e38971df665f4890b1bf7887add536962023-09-12T09:57:07ZengWileyMolecular Genetics & Genomic Medicine2324-92692023-09-01119n/an/a10.1002/mgg3.2215Early onset horizontal gaze palsy and progressive scoliosis due to a noncanonical splicing‐site variant and a missense variant in the ROBO3 geneSheng Yi0Zailong Qin1Xunzhao Zhou2Junjie Chen3Shang Yi4Qiuli Chen5Limei Huang6Qinle Zhang7Biyan Chen8Jingsi Luo9Genetic and Metabolic Central Laboratory Guangxi Birth Defects Research and Prevention Institute, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region Nanning ChinaGenetic and Metabolic Central Laboratory Guangxi Birth Defects Research and Prevention Institute, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region Nanning ChinaGenetic and Metabolic Central Laboratory Guangxi Birth Defects Research and Prevention Institute, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region Nanning ChinaDepartment of Radiology Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region Nanning ChinaGenetic and Metabolic Central Laboratory Guangxi Birth Defects Research and Prevention Institute, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region Nanning ChinaGenetic and Metabolic Central Laboratory Guangxi Birth Defects Research and Prevention Institute, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region Nanning ChinaGenetic and Metabolic Central Laboratory Guangxi Birth Defects Research and Prevention Institute, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region Nanning ChinaGenetic and Metabolic Central Laboratory Guangxi Birth Defects Research and Prevention Institute, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region Nanning ChinaGenetic and Metabolic Central Laboratory Guangxi Birth Defects Research and Prevention Institute, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region Nanning ChinaGenetic and Metabolic Central Laboratory Guangxi Birth Defects Research and Prevention Institute, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region Nanning ChinaAbstract Background Homozygous or compound heterozygous ROBO3 gene mutations cause horizontal gaze palsy with progressive scoliosis (HGPPS). This is an autosomal recessive disorder that is characterized by congenital absence or severe restriction of horizontal gaze and progressive scoliosis. To date, almost 100 patients with HGPPS have been reported and 55 ROBO3 mutations have been identified. Methods We described an HGPPS patient and performed whole‐exome sequencing (WES) to identify the causative gene. Results We identified a missense variant and a splice‐site variant in the ROBO3 gene in the proband. Sanger sequencing of cDNA revealed the presence of an aberrant transcript with retention of 700 bp from intron 17, which was caused by a variation in the noncanonical splicing site. We identified five additional ROBO3 variants, which were likely pathogenic, and estimated the overall allele frequency in the southern Chinese population to be 9.44 × 10−4, by a review of our in‐house database. Conclusion This study has broadened the mutation spectrum of the ROBO3 gene and has expanded our knowledge of variants in noncanonical splicing sites. The results could help to provide more accurate genetic counseling to affected families and prospective couples. We suggest that the ROBO3 gene should be included in the local screening strategy.https://doi.org/10.1002/mgg3.2215allele frequencyHGPPSnoncanonical splicing siteROBO3screening strategy |
| spellingShingle | Sheng Yi Zailong Qin Xunzhao Zhou Junjie Chen Shang Yi Qiuli Chen Limei Huang Qinle Zhang Biyan Chen Jingsi Luo Early onset horizontal gaze palsy and progressive scoliosis due to a noncanonical splicing‐site variant and a missense variant in the ROBO3 gene Molecular Genetics & Genomic Medicine allele frequency HGPPS noncanonical splicing site ROBO3 screening strategy |
| title | Early onset horizontal gaze palsy and progressive scoliosis due to a noncanonical splicing‐site variant and a missense variant in the ROBO3 gene |
| title_full | Early onset horizontal gaze palsy and progressive scoliosis due to a noncanonical splicing‐site variant and a missense variant in the ROBO3 gene |
| title_fullStr | Early onset horizontal gaze palsy and progressive scoliosis due to a noncanonical splicing‐site variant and a missense variant in the ROBO3 gene |
| title_full_unstemmed | Early onset horizontal gaze palsy and progressive scoliosis due to a noncanonical splicing‐site variant and a missense variant in the ROBO3 gene |
| title_short | Early onset horizontal gaze palsy and progressive scoliosis due to a noncanonical splicing‐site variant and a missense variant in the ROBO3 gene |
| title_sort | early onset horizontal gaze palsy and progressive scoliosis due to a noncanonical splicing site variant and a missense variant in the robo3 gene |
| topic | allele frequency HGPPS noncanonical splicing site ROBO3 screening strategy |
| url | https://doi.org/10.1002/mgg3.2215 |
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