Pitfalls of relying on genetic testing only to diagnose inherited metabolic disorders in non-western populations - 5 cases of pyruvate dehydrogenase deficiency from South Africa
| Autor: | Carl Fratter, Surita Meldau, Gillian Riordan, Kate Sergeant, Kashief Khan, Louisa Ntombenhle Bhengu, Peter Berman |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Disease
medicine.disease_cause PDHA1 South Africa Endocrinology Next generation sequencing Genetics medicine Multiple mitochondrial dysfunctions syndrome type 2 Molecular Biology lcsh:QH301-705.5 Genetic testing Mutation lcsh:R5-920 medicine.diagnostic_test biology business.industry PDHC deficiency Pyruvate dehydrogenase complex medicine.disease Pyruvate dehydrogenase deficiency lcsh:Biology (General) GLRX5 SLC19A3 biology.protein SLC19A2 business lcsh:Medicine (General) BOLA3 Research Paper |
| Zdroj: | Molecular Genetics and Metabolism Reports Molecular Genetics and Metabolism Reports, Vol 24, Iss, Pp 100629-(2020) |
| ISSN: | 2214-4269 |
| Popis: | Pyruvate dehydrogenase complex (PDHC) deficiencies are a group of mainly infantile onset disorders stemming from defects in pyruvate catabolism. They are characterised by severe lactic acidosis and progressive neurodegeneration. Although the PDHA1 gene is implicated in most cases of PDHC deficiency worldwide, no pathogenic variants have been reported in South African patients to date, despite availability of PDHA1 sequencing in the state diagnostic setting. Methods DNA from five patients with low to absent PDHC activity in fibroblasts were subjected to PDHC deficiency gene panel analysis. Included in the panel were: PDHA1, PDHB, DLAT, DLD, PDHX, BOLA3, GLRX5, IBA57, LIAS, LIPT1, LIPT2, NFU1, PDP1, PDP2, SLC19A2, SLC19A3, SLC25A19, SLC25A26, TPK1 and FBXL4. Results No pathogenic variants were identified in 4 out of 5 cases investigated. A homozygous frame-shift mutation was detected in the BOLA3 gene in one patient, supporting a diagnosis of multiple mitochondrial dysfunction syndrome type 2. Discussion A single, novel, homozygous BOLA3 frame-shift mutation was detected in a black South African child with severe neurodegenerative disease and very low to absent PDHC enzyme activity. This finding of a homozygous mutation in a patient from a non-consanguineous background may indicate a need for further investigation in clinically similar cases as well as heterozygous carrier rates in unaffected individuals from the same ethnic background. The paucity of identifiable mutations in 4 out of 5 South African patients with confirmed PDHC deficiency highlights the dangers in relying on Western population based genetic panels for diagnosing rare metabolic disease in genetically understudied populations. |
| Databáze: | OpenAIRE |
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