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Research Article
Zhiying Wu
Zhejiang University School of Medicine Second Affiliated Hospital
Corresponding Author
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Background: Although many causative genes have been uncovered in recent years, genetic diagnosis is still missing for approximately 50% of autosomal recessive cerebellar ataxia (ARCA) patients. Few studies have been performed to determine the genetic spectrum and clinical profiles of ARCA patients in the Chinese population.
Methods: Fifty-four Chinese index patients with unexplained autosomal recessive or sporadic ataxia were investigated by whole-exome sequencing (WES) and copy number variation (CNV) calling with Exome Depth. Likely causal CNV predictions were validated by CNVseq.
Results: Thirty-eight mutations including 29 novel ones were identified in 25 out of 54 patients, providing a 46.3% positive molecular diagnostic rate. Ten different genes were involved, and the four most common genes were SACS, SYNE1, ADCK3 and SETX, which accounted for 76.0% (19/25) of the positive cases. The de novo microdeletion in SACS was firstly reported in China and the uniparental disomy of ADCK3 was reported for the first time worldwide. Furthermore, the clinical features of the patients carrying SACS, SYNE1and ADCK3 mutations were summarized.
Conclusions: Our results expand the genetic spectrum and clinical profiles of ARCA patients, demonstrate the high efficiency and reliability of WES combined CNV analysis in diagnosing suspected ARCA, and emphasize the importance of complete bioinformatics analysis of WES data in making an accurate diagnosis.
Keywords
Autosomal recessive cerebellar ataxias, Chinese, Genetic spectrum, Structural variation, Clinical features
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This is a list of supplementary files associated with this preprint. Click to download.
- Additionalfile1SupplementaryFigure1.tif
Additional file 1: Supplementary Figure 1. Reported mutations identified in our ARCA patients. A: Sequencing chromatograms of 9 reported ARCA related mutations. The upper sequence in each frame represents the normal sequence, whereas the lower one represents the variant. B: Sequencing chromatograms of PTPRQ mutations in case 10. C: The pedigree of case 10 with ataxia and hearing loss. Open symbol: unaffected; filled symbol with black or red: affected with ataxia or hearing loss; square: male; circle: female. Genotype data are shown underneath the symbols. Arrowhead: proband of the family. (TIF)
- Additionalfile2SupplementaryVideo1.mp4
Additional file 2: Supplementary Video 1. Myoclonic jerks of face in case 7 with SYNE1 mutations. (MP4)
- Additionalfile3and4SupplementaryTable.xlsx
Additional file 3: Supplementary Table 1. The scale score follow-up of case 15 with ADCK3 mutation after supply COQ10. (XLSX) Additional file 4: Supplementary Table 2. Clinical features of ARSACS patients in China. (XLSX)
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CURRENT STATUS: Under Review
Version 1
Posted 12 Jun, 2021
No community comments so far
Editorial decision: Major revision
On 23 Jun, 2021
Review #1 received
Received 21 Jun, 2021
Review #2 received
Received 19 Jun, 2021
Reviewer #2 agreed
On 08 Jun, 2021
Reviews received
Received 07 Jun, 2021
Reviewer #1 agreed
On 06 Jun, 2021
Reviewers invited
Invitations sent on 04 Jun, 2021
Editor invited
On 04 Jun, 2021
Editor assigned
On 31 May, 2021
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On 31 May, 2021
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This preprint is under consideration at Translational Neurodegeneration. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research Article
Zhiying Wu
Zhejiang University School of Medicine Second Affiliated Hospital
Corresponding Author
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Review
Version 1
Posted 12 Jun, 2021
No community comments so far
Editorial decision: Major revision
On 23 Jun, 2021
Review #1 received
Received 21 Jun, 2021
Review #2 received
Received 19 Jun, 2021
Reviewer #2 agreed
On 08 Jun, 2021
Reviews received
Received 07 Jun, 2021
Reviewer #1 agreed
On 06 Jun, 2021
Reviewers invited
Invitations sent on 04 Jun, 2021
Editor invited
On 04 Jun, 2021
Editor assigned
On 31 May, 2021
Submission checks complete
On 31 May, 2021
First submitted
On 30 May, 2021
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background: Although many causative genes have been uncovered in recent years, genetic diagnosis is still missing for approximately 50% of autosomal recessive cerebellar ataxia (ARCA) patients. Few studies have been performed to determine the genetic spectrum and clinical profiles of ARCA patients in the Chinese population.
Methods: Fifty-four Chinese index patients with unexplained autosomal recessive or sporadic ataxia were investigated by whole-exome sequencing (WES) and copy number variation (CNV) calling with Exome Depth. Likely causal CNV predictions were validated by CNVseq.
Results: Thirty-eight mutations including 29 novel ones were identified in 25 out of 54 patients, providing a 46.3% positive molecular diagnostic rate. Ten different genes were involved, and the four most common genes were SACS, SYNE1, ADCK3 and SETX, which accounted for 76.0% (19/25) of the positive cases. The de novo microdeletion in SACS was firstly reported in China and the uniparental disomy of ADCK3 was reported for the first time worldwide. Furthermore, the clinical features of the patients carrying SACS, SYNE1and ADCK3 mutations were summarized.
Conclusions: Our results expand the genetic spectrum and clinical profiles of ARCA patients, demonstrate the high efficiency and reliability of WES combined CNV analysis in diagnosing suspected ARCA, and emphasize the importance of complete bioinformatics analysis of WES data in making an accurate diagnosis.
Figure 1
Figure 2
Figure 3
Figure 4
This is a list of supplementary files associated with this preprint. Click to download.
- Additionalfile1SupplementaryFigure1.tif
Additional file 1: Supplementary Figure 1. Reported mutations identified in our ARCA patients. A: Sequencing chromatograms of 9 reported ARCA related mutations. The upper sequence in each frame represents the normal sequence, whereas the lower one represents the variant. B: Sequencing chromatograms of PTPRQ mutations in case 10. C: The pedigree of case 10 with ataxia and hearing loss. Open symbol: unaffected; filled symbol with black or red: affected with ataxia or hearing loss; square: male; circle: female. Genotype data are shown underneath the symbols. Arrowhead: proband of the family. (TIF)
- Additionalfile2SupplementaryVideo1.mp4
Additional file 2: Supplementary Video 1. Myoclonic jerks of face in case 7 with SYNE1 mutations. (MP4)
- Additionalfile3and4SupplementaryTable.xlsx
Additional file 3: Supplementary Table 1. The scale score follow-up of case 15 with ADCK3 mutation after supply COQ10. (XLSX) Additional file 4: Supplementary Table 2. Clinical features of ARSACS patients in China. (XLSX)
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