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Combined Genome, Transcriptome and Metabolome Analysis in the Diagnosis of Childhood Cerebellar Ataxia
Ataxia in children is a common clinical sign of numerous neurological disorders consisting of impaired coordination of voluntary muscle movement. Its most common form, cerebellar ataxia, describes a heterogeneous array of neurologic conditions with uncountable causes broadly divided as acquired or g...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002209/ https://www.ncbi.nlm.nih.gov/pubmed/33804237 http://dx.doi.org/10.3390/ijms22062990 |
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author | Ching-López, Ana Martinez-Gonzalez, Luis Javier Arrabal, Luisa Sáiz, Jorge Gavilán, Ángela Barbas, Coral Lorente, Jose Antonio Roldán, Susana Sánchez, Maria José Gutierrez-Ríos, Purificacion |
author_facet | Ching-López, Ana Martinez-Gonzalez, Luis Javier Arrabal, Luisa Sáiz, Jorge Gavilán, Ángela Barbas, Coral Lorente, Jose Antonio Roldán, Susana Sánchez, Maria José Gutierrez-Ríos, Purificacion |
author_sort | Ching-López, Ana |
collection | PubMed |
description | Ataxia in children is a common clinical sign of numerous neurological disorders consisting of impaired coordination of voluntary muscle movement. Its most common form, cerebellar ataxia, describes a heterogeneous array of neurologic conditions with uncountable causes broadly divided as acquired or genetic. Numerous genetic disorders are associated with chronic progressive ataxia, which complicates clinical management, particularly on the diagnostic stage. Advances in omics technologies enable improvements in clinical practice and research, so we proposed a multi-omics approach to aid in the genetic diagnosis and molecular elucidation of an undiagnosed infantile condition of chronic progressive cerebellar ataxia. Using whole-exome sequencing, RNA-seq, and untargeted metabolomics, we identified three clinically relevant mutations (rs141471029, rs191582628 and rs398124292) and an altered metabolic profile in our patient. Two POLR1C diagnostic variants already classified as pathogenic were found, and a diagnosis of hypomyelinating leukodystrophy was achieved. A mutation on the MMACHC gene, known to be associated with methylmalonic aciduria and homocystinuria cblC type, was also found. Additionally, preliminary metabolome analysis revealed alterations in our patient’s amino acid, fatty acid and carbohydrate metabolism. Our findings provided a definitive genetic diagnosis reinforcing the association between POLR1C mutations and hypomyelinating leukodystrophy and highlighted the relevance of multi-omics approaches to the disease. |
format | Online Article Text |
id | pubmed-8002209 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-80022092021-03-28 Combined Genome, Transcriptome and Metabolome Analysis in the Diagnosis of Childhood Cerebellar Ataxia Ching-López, Ana Martinez-Gonzalez, Luis Javier Arrabal, Luisa Sáiz, Jorge Gavilán, Ángela Barbas, Coral Lorente, Jose Antonio Roldán, Susana Sánchez, Maria José Gutierrez-Ríos, Purificacion Int J Mol Sci Article Ataxia in children is a common clinical sign of numerous neurological disorders consisting of impaired coordination of voluntary muscle movement. Its most common form, cerebellar ataxia, describes a heterogeneous array of neurologic conditions with uncountable causes broadly divided as acquired or genetic. Numerous genetic disorders are associated with chronic progressive ataxia, which complicates clinical management, particularly on the diagnostic stage. Advances in omics technologies enable improvements in clinical practice and research, so we proposed a multi-omics approach to aid in the genetic diagnosis and molecular elucidation of an undiagnosed infantile condition of chronic progressive cerebellar ataxia. Using whole-exome sequencing, RNA-seq, and untargeted metabolomics, we identified three clinically relevant mutations (rs141471029, rs191582628 and rs398124292) and an altered metabolic profile in our patient. Two POLR1C diagnostic variants already classified as pathogenic were found, and a diagnosis of hypomyelinating leukodystrophy was achieved. A mutation on the MMACHC gene, known to be associated with methylmalonic aciduria and homocystinuria cblC type, was also found. Additionally, preliminary metabolome analysis revealed alterations in our patient’s amino acid, fatty acid and carbohydrate metabolism. Our findings provided a definitive genetic diagnosis reinforcing the association between POLR1C mutations and hypomyelinating leukodystrophy and highlighted the relevance of multi-omics approaches to the disease. MDPI 2021-03-15 /pmc/articles/PMC8002209/ /pubmed/33804237 http://dx.doi.org/10.3390/ijms22062990 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Ching-López, Ana Martinez-Gonzalez, Luis Javier Arrabal, Luisa Sáiz, Jorge Gavilán, Ángela Barbas, Coral Lorente, Jose Antonio Roldán, Susana Sánchez, Maria José Gutierrez-Ríos, Purificacion Combined Genome, Transcriptome and Metabolome Analysis in the Diagnosis of Childhood Cerebellar Ataxia |
title | Combined Genome, Transcriptome and Metabolome Analysis in the Diagnosis of Childhood Cerebellar Ataxia |
title_full | Combined Genome, Transcriptome and Metabolome Analysis in the Diagnosis of Childhood Cerebellar Ataxia |
title_fullStr | Combined Genome, Transcriptome and Metabolome Analysis in the Diagnosis of Childhood Cerebellar Ataxia |
title_full_unstemmed | Combined Genome, Transcriptome and Metabolome Analysis in the Diagnosis of Childhood Cerebellar Ataxia |
title_short | Combined Genome, Transcriptome and Metabolome Analysis in the Diagnosis of Childhood Cerebellar Ataxia |
title_sort | combined genome, transcriptome and metabolome analysis in the diagnosis of childhood cerebellar ataxia |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002209/ https://www.ncbi.nlm.nih.gov/pubmed/33804237 http://dx.doi.org/10.3390/ijms22062990 |
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