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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
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.
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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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