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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

1
Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
2
National Centre for Inherited Metabolic Disorders, Temple Street Children's University Hospital, Dublin, Ireland.
3
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.
4
Department of Metabolic Paediatrics, Royal Hospital for Sick Children, Belfast, UK.
5
University of Bristol and Bristol Royal Hospital for Children, Bristol, UK.
6
Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, London, UK.
7
Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
8
Department of Paediatrics, The Royal Children's Hospital, Murdoch Children's Research Institute, University of Melbourne, Parkville, Australia.
9
Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.

Abstract

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.

KEYWORDS:

complex I deficiency; dysmorphic features; mitochondrial disease; prognosis

PMID:
27091925
PMCID:
PMC5013090
DOI:
10.1136/jmedgenet-2015-103576
[Indexed for MEDLINE]
Free PMC Article

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