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J Med Genet. 2016 Sep;53(9):634-41. doi: 10.1136/jmedgenet-2015-103576. Epub 2016 Apr 18.

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

Author information

Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
National Centre for Inherited Metabolic Disorders, Temple Street Children's University Hospital, Dublin, Ireland.
Centre for Paediatrics and Child Health, Institute of Human Development, Faculty of Medical & Human Sciences, University of Manchester, & Manchester Academic Health Science Centre, Manchester, UK.
Department of Metabolic Paediatrics, Royal Hospital for Sick Children, Belfast, UK.
University of Bristol and Bristol Royal Hospital for Children, Bristol, UK.
Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, London, UK.
Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
Department of Paediatrics, The Royal Children's Hospital, Murdoch Children's Research Institute, University of Melbourne, Parkville, Australia.
Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.



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.


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


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.


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.


complex I deficiency; dysmorphic features; mitochondrial disease; prognosis

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