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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MDPI AG
2021-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/6/2990 |
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| author | Ana Ching-López Luis Javier Martinez-Gonzalez Luisa Arrabal Jorge Sáiz Ángela Gavilán Coral Barbas Jose Antonio Lorente Susana Roldán Maria José Sánchez Purificacion Gutierrez-Ríos |
| author_facet | Ana Ching-López Luis Javier Martinez-Gonzalez Luisa Arrabal Jorge Sáiz Ángela Gavilán Coral Barbas Jose Antonio Lorente Susana Roldán Maria José Sánchez Purificacion Gutierrez-Ríos |
| author_sort | Ana Ching-López |
| collection | DOAJ |
| 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 <i>POLR1C</i> diagnostic variants already classified as pathogenic were found, and a diagnosis of hypomyelinating leukodystrophy was achieved. A mutation on the <i>MMACHC</i> 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 <i>POLR1C</i> mutations and hypomyelinating leukodystrophy and highlighted the relevance of multi-omics approaches to the disease. |
| first_indexed | 2024-03-10T13:12:41Z |
| format | Article |
| id | doaj.art-83692fc3457f42c1a42a63fa0f950130 |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T13:12:41Z |
| publishDate | 2021-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-83692fc3457f42c1a42a63fa0f9501302023-11-21T10:36:36ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-03-01226299010.3390/ijms22062990Combined Genome, Transcriptome and Metabolome Analysis in the Diagnosis of Childhood Cerebellar AtaxiaAna Ching-López0Luis Javier Martinez-Gonzalez1Luisa Arrabal2Jorge Sáiz3Ángela Gavilán4Coral Barbas5Jose Antonio Lorente6Susana Roldán7Maria José Sánchez8Purificacion Gutierrez-Ríos9CIBER Epidemiology and Public Health (CIBERESP), 28029 Madrid, SpainGENYO, Centre for Genomics and Oncological Research, Pfizer, University of Granada, Andalusian Regional Government, PTS Granada, 18016 Granada, SpainPediatric Neurology Department, Hospital Virgen de las Nieves, 18014 Granada, SpainCentre for Metabolomics and Bioanalysis (CEMBIO), Chemistry and Biochemistry Department, Pharmacy Faculty, Universidad San Pablo-CEU, 28925 Madrid, SpainInstitute of Biomedicine of Seville (IBIS), 41013 Seville, SpainCentre for Metabolomics and Bioanalysis (CEMBIO), Chemistry and Biochemistry Department, Pharmacy Faculty, Universidad San Pablo-CEU, 28925 Madrid, SpainGENYO, Centre for Genomics and Oncological Research, Pfizer, University of Granada, Andalusian Regional Government, PTS Granada, 18016 Granada, SpainPediatric Neurology Department, Hospital Virgen de las Nieves, 18014 Granada, SpainCIBER Epidemiology and Public Health (CIBERESP), 28029 Madrid, SpainInstituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, SpainAtaxia 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 <i>POLR1C</i> diagnostic variants already classified as pathogenic were found, and a diagnosis of hypomyelinating leukodystrophy was achieved. A mutation on the <i>MMACHC</i> 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 <i>POLR1C</i> mutations and hypomyelinating leukodystrophy and highlighted the relevance of multi-omics approaches to the disease.https://www.mdpi.com/1422-0067/22/6/2990cerebellar ataxiadiagnosisgenomicstranscriptomicsmetabolomicshypomyelination |
| spellingShingle | Ana Ching-López Luis Javier Martinez-Gonzalez Luisa Arrabal Jorge Sáiz Ángela Gavilán Coral Barbas Jose Antonio Lorente Susana Roldán Maria José Sánchez Purificacion Gutierrez-Ríos Combined Genome, Transcriptome and Metabolome Analysis in the Diagnosis of Childhood Cerebellar Ataxia International Journal of Molecular Sciences cerebellar ataxia diagnosis genomics transcriptomics metabolomics hypomyelination |
| 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 | cerebellar ataxia diagnosis genomics transcriptomics metabolomics hypomyelination |
| url | https://www.mdpi.com/1422-0067/22/6/2990 |
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