Combined Genome, Transcriptome and Metabolome Analysis in the Diagnosis of Childhood Cerebellar Ataxia Ching López, Ana Martínez González, Luis Javier Arrabal, Luisa Sáiz, Jorge Gavilán, Ángela Barbas, Coral Lorente Acosta, José Antonio Roldán, Susana Sánchez Pérez, María José Gutiérrez Ríos, Purificación Cerebellar ataxia Diagnosis Genomics Transcriptomics Metabolomics Hypomyelination Leukodystrophy POLR1C Supplementary Materials: Supplementary Materials can be found at https://www.mdpi.com/1422 -0067/22/6/2990/s1. The project was approved by the Biomedical Research Ethics Committee of the Andalusian Public Health System in Granada, Spain on Oct. 29, 2015, (project identification code AP163052016). Data recording, sample collection and all in vitro experiments were conducted in accordance with ethical guidelines following the Nuremberg Code, Belmont Report, and the Declaration of Helsinki. Acknowledgments: We are grateful for the support and cooperation of the subjects, as well as their families. 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. 2021-05-07T11:24:06Z 2021-05-07T11:24:06Z 2021-03-15 journal article Ching-López, A.; Martinez-Gonzalez, L.J.; Arrabal, L.; Sáiz, J.; Gavilán, Á.; Barbas, C.; Lorente, J.A.; Roldán, S.; Sánchez, M.J.; Gutierrez-Ríos, P. Combined Genome, Transcriptome and Metabolome Analysis in the Diagnosis of Childhood Cerebellar Ataxia. Int. J. Mol. Sci. 2021, 22, 2990. [https://doi.org/10.3390/ijms22062990] http://hdl.handle.net/10481/68393 10.3390/ijms22062990 eng http://creativecommons.org/licenses/by/3.0/es/ open access Atribución 3.0 España MDPI