%0 Journal Article %A Charlotte L Alston %A Caoimhe Howard %A Monika Oláhová %A Steven A Hardy %A Langping He %A Philip G Murray %A Siobhan O'Sullivan %A Gary Doherty %A Julian P H Shield %A Iain P Hargreaves %A Ardeshir A Monavari %A Ina Knerr %A Peter McCarthy %A Andrew A M Morris %A David R Thorburn %A Holger Prokisch %A Peter E Clayton %A Robert McFarland %A Joanne Hughes %A Ellen Crushell %A Robert W Taylor %T A recurrent mitochondrial p.Trp22Arg NDUFB3 variant causes a distinctive facial appearance, short stature and a mild biochemical and clinical phenotype %D 2016 %R 10.1136/jmedgenet-2015-103576 %J Journal of Medical Genetics %P 634-641 %V 53 %N 9 %X 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 (<9th centile) and similar facial features including a prominent forehead, smooth philtrum and deep-set eyes associated with a recurrent homozygous c.64T>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. %U https://jmg.bmj.com/content/jmedgenet/53/9/634.full.pdf