Application of exome sequencing in the molecular diagnosis of inborn errors of metabolism: first experience at the Centro de Estudio de las Metabolopatías Congénitas (CEMECO) in Córdoba, Argentina.
Inborn errors of metabolism (IEM) are monogenic defects with great phenotypic and genetic variability. The study of patients with clinical suspicion of IEM includes first-line biochemical studies (metabolites in biological fluids) that guide specific enzymatic and/or genetic analyses. This diagnosti...
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| Autores principales: | , , , , , , , |
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| Formato: | Artículo revista |
| Lenguaje: | Español |
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Universidad Nacional Córdoba. Facultad de Ciencias Médicas. Secretaria de Ciencia y Tecnología
2023
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| Acceso en línea: | https://revistas.unc.edu.ar/index.php/med/article/view/42681 |
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| Sumario: | Inborn errors of metabolism (IEM) are monogenic defects with great phenotypic and genetic variability. The study of patients with clinical suspicion of IEM includes first-line biochemical studies (metabolites in biological fluids) that guide specific enzymatic and/or genetic analyses. This diagnostic strategy, from phenotype to genotype, is effective when the clinical characteristics are highly suggestive and associated with specific biomarkers. In contrast, in complex diseases that do not present typical biochemical alterations, exome sequencing appears to be an effective and promising diagnostic tool. The objective of this work is to show the first experience in CEMECO of the application of exome sequencing for the molecular diagnosis of EIM.
Exome sequencing was performed in 50 patients with clinical and/or biochemical suspicion of IEM studied at CEMECO (April-2022/March-2023). Genomic DNA was purified from whole blood by Roche MagNA, and sequencing and analysis of exome data were performed by 3billion company (South Korea). The identified variants were classified according to the consensus criteria of the American College of Medical Genetics and Genomics.
The overall diagnosis rate was 54% (27/50): 21/27 patients with IEM (10 with high clinical-biochemical suspicion and 11 with non-specific clinical-biochemical findings) and 6/27 individuals with other genetic diseases, not IEM. In 3 patients, 2 coexisting genetic diseases were detected and in another 3 incidental findings were identified in genes associated with risk factors. The IEM identified included: aminoacidopathies (33.3%), organic acidurias (19.0%), mitochondriopathies (19.0%), fatty acid β-oxidation defects (14.4%), disorders of vitamins and cofactors (9.5%) and urea cycle defects (4.8%). Forty-one different genetic variants corresponding to 23 genes were identified, classified as: pathogenic (53.7%), probably pathogenic (19.5%) and of uncertain significance (26.8%).
Exome sequencing is an effective methodology in the diagnosis of metabolic and neurogenetic diseases (specially in complex or unresolved cases) allowing personalized, predictive and/or preventive medicine. Exome sequencing has revolutionized clinical practice by changing the paradigm to “reverse genomic medicine”: from genotype to phenotype. |
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