Ching-López, AnaMartinez-Gonzalez, Luis JavierArrabal, LuisaSáiz, JorgeGavilán, ÁngelaBarbas, CoralLorente, Jose AntonioRoldán, SusanaSanchez-Perez, Maria-JoseGutierrez-Ríos, Purificacion2022-09-202022-09-202021-03-15Ching-López A, Martinez-Gonzalez LJ, Arrabal L, Sáiz J, Gavilán Á, Barbas C, et al. Combined Genome, Transcriptome and Metabolome Analysis in the Diagnosis of Childhood Cerebellar Ataxia. Int J Mol Sci. 2021 Mar 15;22(6):2990http://hdl.handle.net/10668/4074Ataxia 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.enAtribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/Cerebellar ataxiaDiagnosisGenomicsTranscriptomicsMetabolomicsHypomyelinationLeukodystrophyPOLR1CAtaxia cerebelosaDiagnósticoGenómicaMetabolómicaLeucoencefalopatíasARN polimerasa IMedical Subject Headings::Persons::Persons::Age Groups::AdolescentMedical Subject Headings::Persons::Persons::Age Groups::AdultMedical Subject Headings::Diseases::Nervous System Diseases::Central Nervous System Diseases::Brain Diseases::Cerebellar Diseases::Cerebellar AtaxiaMedical Subject Headings::Persons::Persons::Age Groups::ChildMedical Subject Headings::Persons::Persons::Age Groups::Child::Child, PreschoolMedical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Nucleotidyltransferases::RNA Nucleotidyltransferases::DNA-Directed RNA PolymerasesMedical Subject Headings::Check Tags::FemaleMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Structures::GenomeMedical Subject Headings::Check Tags::MaleMedical Subject Headings::Phenomena and Processes::Metabolic Phenomena::MetabolomeMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Variation::MutationMedical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::OxidoreductasesMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::PedigreeMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression::Transcription, Genetic::TranscriptomeMedical Subject Headings::Diseases::Nutritional and Metabolic Diseases::Nutrition Disorders::Malnutrition::Deficiency Diseases::Avitaminosis::Vitamin B Deficiency::Vitamin B 12 DeficiencyMedical Subject Headings::Persons::Persons::Age Groups::Adult::Young Adultresearch article33804237open access10.3390/ijms220629901422-0067PMC8002209