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

• Published in: Journal of medical genetics Vol. 53; no. 9; pp. 634 - 641
• Main Authors: Alston, Charlotte L, Howard, Caoimhe, Oláhová, Monika, Hardy, Steven A, He, Langping, Murray, Philip G, O'Sullivan, Siobhan, Doherty, Gary, Shield, Julian P H, Hargreaves, Iain P, Monavari, Ardeshir A, Knerr, Ina, McCarthy, Peter, Morris, Andrew A M, Thorburn, David R, Prokisch, Holger, Clayton, Peter E, McFarland, Robert, Hughes, Joanne, Crushell, Ellen, Taylor, Robert W
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group 01.09.2016
• Series: Short report
• Subjects: Child; Child, Preschool; Dwarfism - genetics; Electron Transport Complex I - genetics; Exome - genetics; Facies; Female; Genetic Association Studies - methods; Genotype-Phenotype Correlations; Homozygote; Humans; Infant; Male; Mitochondria - genetics; Mitochondrial Diseases - genetics; Mutation - genetics; Pedigree; Phenotype; complex I deficiency; prognosis; dysmorphic features; mitochondrial disease
• ISSN: 0022-2593; 1468-6244
• DOI: 10.1136/jmedgenet-2015-103576

BackgroundIsolated 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.MethodsPatients were analysed by whole-exome sequencing, targeted capture or candidate gene sequencing. Clinical phenotyping of affected individuals was performed.ResultsWe 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.ConclusionsOur 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.