Identification of a single MPV17 nonsense-associated altered splice variant in 24 South African infants with mitochondrial neurohepatopathy

Abstract

MPV17-related mitochondrial neurohepatopathy is a rare genetic disorder worldwide. We report on a novel pathogenic variant in the MPV17 gene in 24 unrelated neurohepatopathic infants of non-consanguineous Black South African heritage.

Exome sequencing identified homozygosity for a c.106C>T nonsense variant in exon 3 of the human MPV17 gene in two unrelated index patients. mRNA analysis revealed transcripts both with and without exon 3, indicating both reduced splice efficiency and premature termination as mechanisms for disease. Carrier frequency in this population was found to be 1 in 68 (95% CI; 1/122 – 1/38) with an estimated newborn incidence of 1 in 18496 (95% CI; 1/59536 – 1/5776). Affected infants all presented with infantile onset neurohepatopathy with none surviving beyond infancy. This description of a relatively common pathogenic variant underlying a previously uncharacterised severe neurohepatopathy in South Africa will engender increased awareness, earlier diagnosis and possibly improve outcome if preventative or specific therapeutic options can be found.

Exome sequencing reveals homozygous nonsense mutation (c.106C>T) in MPV17 in 24 Black South African patients with mitochondrial neurohepatopathy. The variant is shown to result in 2 nonsense transcripts: One caused by the introduction of a premature stop codon (p.Gln36Ter) and the second due to nonsense-associated alternative splicing caused by a reduction in exonic splice enhancer efficiency (p.Ser25Profs*49).

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