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Genetic spectrum and clinical features in a cohort of Chinese patients with autosomal recessive cerebellar ataxias

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 profile of ARCA patients in...

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Autores principales: Cheng, Hao-Ling, Shao, Ya-Ru, Dong, Yi, Dong, Hai-Lin, Yang, Lu, Ma, Yin, Shen, Ying, Wu, Zhi-Ying
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8522248/
https://www.ncbi.nlm.nih.gov/pubmed/34663476
http://dx.doi.org/10.1186/s40035-021-00264-z
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author Cheng, Hao-Ling
Shao, Ya-Ru
Dong, Yi
Dong, Hai-Lin
Yang, Lu
Ma, Yin
Shen, Ying
Wu, Zhi-Ying
author_facet Cheng, Hao-Ling
Shao, Ya-Ru
Dong, Yi
Dong, Hai-Lin
Yang, Lu
Ma, Yin
Shen, Ying
Wu, Zhi-Ying
author_sort Cheng, Hao-Ling
collection PubMed
description 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 profile 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 ExomeDepth. Likely causal CNV predictions were validated by CNVseq. RESULTS: Thirty-eight mutations including 29 novel ones were identified in 25 out of the 54 patients, providing a 46.3% positive molecular diagnostic rate. Ten different genes were involved, of which 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 reported for the first time in China and the uniparental disomy of ADCK3 was reported for the first time worldwide. Clinical features of the patients carrying SACS, SYNE1 and 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 with CNV analysis in the diagnosis of suspected ARCA, and emphasize the importance of complete bioinformatics analysis of WES data for accurate diagnosis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40035-021-00264-z.
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spelling pubmed-85222482021-10-22 Genetic spectrum and clinical features in a cohort of Chinese patients with autosomal recessive cerebellar ataxias Cheng, Hao-Ling Shao, Ya-Ru Dong, Yi Dong, Hai-Lin Yang, Lu Ma, Yin Shen, Ying Wu, Zhi-Ying Transl Neurodegener Research 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 profile 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 ExomeDepth. Likely causal CNV predictions were validated by CNVseq. RESULTS: Thirty-eight mutations including 29 novel ones were identified in 25 out of the 54 patients, providing a 46.3% positive molecular diagnostic rate. Ten different genes were involved, of which 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 reported for the first time in China and the uniparental disomy of ADCK3 was reported for the first time worldwide. Clinical features of the patients carrying SACS, SYNE1 and 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 with CNV analysis in the diagnosis of suspected ARCA, and emphasize the importance of complete bioinformatics analysis of WES data for accurate diagnosis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40035-021-00264-z. BioMed Central 2021-10-18 /pmc/articles/PMC8522248/ /pubmed/34663476 http://dx.doi.org/10.1186/s40035-021-00264-z Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Cheng, Hao-Ling
Shao, Ya-Ru
Dong, Yi
Dong, Hai-Lin
Yang, Lu
Ma, Yin
Shen, Ying
Wu, Zhi-Ying
Genetic spectrum and clinical features in a cohort of Chinese patients with autosomal recessive cerebellar ataxias
title Genetic spectrum and clinical features in a cohort of Chinese patients with autosomal recessive cerebellar ataxias
title_full Genetic spectrum and clinical features in a cohort of Chinese patients with autosomal recessive cerebellar ataxias
title_fullStr Genetic spectrum and clinical features in a cohort of Chinese patients with autosomal recessive cerebellar ataxias
title_full_unstemmed Genetic spectrum and clinical features in a cohort of Chinese patients with autosomal recessive cerebellar ataxias
title_short Genetic spectrum and clinical features in a cohort of Chinese patients with autosomal recessive cerebellar ataxias
title_sort genetic spectrum and clinical features in a cohort of chinese patients with autosomal recessive cerebellar ataxias
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8522248/
https://www.ncbi.nlm.nih.gov/pubmed/34663476
http://dx.doi.org/10.1186/s40035-021-00264-z
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