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

Surita Meldau; Carl Fratter; Louisa Ntombenhle Bhengu; Kate Sergeant; Kashief Khan; Gillian Tracy Riordan; Peter Allan Minham Berman

doi:10.1016/j.ymgmr.2020.100629

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

Mol Genet Metab Rep. 2020 Jul 22:24:100629. doi: 10.1016/j.ymgmr.2020.100629. eCollection 2020 Sep.

Authors

Surita Meldau^{1

2}, Carl Fratter³, Louisa Ntombenhle Bhengu⁴, Kate Sergeant³, Kashief Khan¹, Gillian Tracy Riordan⁵, Peter Allan Minham Berman^{1

2}

Affiliations

¹ National Health Laboratory Service (NHLS), Cape Town, South Africa.
² Division of Chemical Pathology, Department of Pathology, University of Cape Town (UCT), Cape Town, South Africa.
³ Oxford Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
⁴ Department of Human Genetics, National Health Laboratory Service and School of Pathology, University of Witwatersrand, Johannesburg, South Africa.
⁵ Paediatric Neurology Department of Paediatrics and Child Health Red Cross War Memorial Children's Hospital, University of Cape Town, Cape Town, South Africa.

Abstract

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.

Keywords: BOLA3; Multiple mitochondrial dysfunctions syndrome type 2; Next generation sequencing; PDHA1; PDHC deficiency; South Africa.