TY - JOUR T1 - A recurrent mitochondrial p.Trp22Arg <em>NDUFB3</em> variant causes a distinctive facial appearance, short stature and a mild biochemical and clinical phenotype JF - Journal of Medical Genetics JO - J Med Genet SP - 634 LP - 641 DO - 10.1136/jmedgenet-2015-103576 VL - 53 IS - 9 AU - Charlotte L Alston AU - Caoimhe Howard AU - Monika Oláhová AU - Steven A Hardy AU - Langping He AU - Philip G Murray AU - Siobhan O'Sullivan AU - Gary Doherty AU - Julian P H Shield AU - Iain P Hargreaves AU - Ardeshir A Monavari AU - Ina Knerr AU - Peter McCarthy AU - Andrew A M Morris AU - David R Thorburn AU - Holger Prokisch AU - Peter E Clayton AU - Robert McFarland AU - Joanne Hughes AU - Ellen Crushell AU - Robert W Taylor Y1 - 2016/09/01 UR - http://jmg.bmj.com/content/53/9/634.abstract N2 - 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 (&lt;9th centile) and similar facial features including a prominent forehead, smooth philtrum and deep-set eyes associated with a recurrent homozygous c.64T&gt;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. ER -