A recurrent mitochondrial p.Trp22Arg NDUFB3 variant causes a distinctive facial appearance, short stature and a mild biochemical and clinical phenotype

Charlotte L. Alston, Caoimhe Howard, Monika Oláhová, Steven A. Hardy, Langping He, Philip G. Murray, Siobhan O'Sullivan, Gary Doherty, Julian P Hamilton-Shield, Iain P. Hargreaves, Ardeshir A. Monavari, Ina Knerr, Peter W McCarthy, Andrew A M Morris, David R. Thorburn, Holger Prokisch, Peter Clayton, Robert McFarland, Joanne Hughes, Ellen CrushellRobert W. Taylor*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

16 Citations (Scopus)
218 Downloads (Pure)


Background Isolated Complex I deficiency is the most common paediatric mitochondrial disease presentation, associated with poor prognosis and high mortality. Complex I comprises 44 structural subunits with at least 10 ancillary proteins; mutations in 29 of these have so far been associated with mitochondrial disease but there are limited genotype-phenotype correlations to guide clinicians to the correct genetic diagnosis. 

Methods Patients were analysed by whole-exome sequencing, targeted capture or candidate gene sequencing. Clinical phenotyping of affected individuals was performed. 

Results We identified a cohort of 10 patients from 8 families (7 families are of unrelated Irish ancestry) all of whom have short stature (C, p.Trp22Arg NDUFB3 variant. Two sibs presented with primary short stature without obvious metabolic dysfunction. Analysis of skeletal muscle from three patients confirmed a defect in Complex I assembly. 

Conclusions Our report highlights that the long-term prognosis related to the p.Trp22Arg NDUFB3 mutation can be good, even for some patients presenting in acute metabolic crisis with evidence of an isolated Complex I deficiency in muscle. Recognition of the distinctive facial features-particularly when associated with markers of mitochondrial dysfunction and/or Irish ancestry-should suggest screening for the p.Trp22Arg NDUFB3 mutation to establish a genetic diagnosis, circumventing the requirement of muscle biopsy to direct genetic investigations.

Original languageEnglish
Pages (from-to)634-641
Number of pages8
JournalJournal of Medical Genetics
Issue number9
Early online date18 Apr 2016
Publication statusPublished - Sep 2016


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