A recurrent mitochondrial p.Trp22Arg NDUFB3 variant causes a distinctive facial appearance, short stature and a mild biochemical and clinical phenotype.
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.
Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
Charlotte L
CL
Alston
National Centre for Inherited Metabolic Disorders, Temple Street Children's University Hospital, Dublin, Ireland.
Caoimhe
C
Howard
Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
Monika
M
Oláhová
Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
Steven A
SA
Hardy
Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
Langping
L
He
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.
Philip G
PG
Murray
Department of Metabolic Paediatrics, Royal Hospital for Sick Children, Belfast, UK.
Siobhan
S
O'Sullivan
Department of Metabolic Paediatrics, Royal Hospital for Sick Children, Belfast, UK.
Gary
G
Doherty
University of Bristol and Bristol Royal Hospital for Children, Bristol, UK.
Julian P H
JP
Shield
Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, London, UK.
Iain P
IP
Hargreaves
National Centre for Inherited Metabolic Disorders, Temple Street Children's University Hospital, Dublin, Ireland.
Ardeshir A
AA
Monavari
National Centre for Inherited Metabolic Disorders, Temple Street Children's University Hospital, Dublin, Ireland.
Ina
I
Knerr
National Centre for Inherited Metabolic Disorders, Temple Street Children's University Hospital, Dublin, Ireland.
Peter
P
McCarthy
Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
Andrew A M
AA
Morris
Department of Paediatrics, The Royal Children's Hospital, Murdoch Children's Research Institute, University of Melbourne, Parkville, Australia.
David R
DR
Thorburn
Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
Holger
H
Prokisch
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.
Peter E
PE
Clayton
Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
Robert
R
McFarland
National Centre for Inherited Metabolic Disorders, Temple Street Children's University Hospital, Dublin, Ireland.
Joanne
J
Hughes
National Centre for Inherited Metabolic Disorders, Temple Street Children's University Hospital, Dublin, Ireland.
Ellen
E
Crushell
Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
Robert W
RW
Taylor
D002648:Child; D002675:Child, Preschool; D004392:Dwarfism / Q000235:genetics*; D042967:Electron Transport Complex I / Q000235:genetics*; D059472:Exome / Q000235:genetics; D019066:Facies; D005260:Female; D056726:Genetic Association Studies / Q000379:methods; D006720:Homozygote; D006801:Humans; D007223:Infant; D008297:Male; D008928:Mitochondria / Q000235:genetics*; D028361:Mitochondrial Diseases / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype
D042967:Electron Transport Complex I
complex I deficiency; dysmorphic features; mitochondrial disease; prognosis