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Alston, CL, Howard, C, Olahova, M, Hardy, SA, He, L, Murray, PG, O'Sullivan, S, Doherty, G, Shield, JPH, Hargreaves, IP, Monavari, AA, Knerr, I, McCarthy, P, Morris, AAM, Thorburn, DR, Prokisch, H, Clayton, PE, McFarland, R, Hughes, J, Crushell, E and Taylor, RW (2016) A recurrent mitochondrial p.Trp22Arg NDUFB3 variant causes a distinctive facial appearance, short stature and a mild biochemical and clinical phenotype. Journal of Medical Genetics (JMG), 53 (9). pp. 634-641. ISSN 0022-2593
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A recurrent mitochondrial p.Trp22Arg NDUFB3 variant causes a distinctive facial appearance, short stature and a mild biochem.pdf - Published Version Available under License Creative Commons Attribution. Download (3MB) | Preview |
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.
| Item Type: | Article |
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| Uncontrolled Keywords: | 06 Biological Sciences, 11 Medical and Health Sciences |
| Subjects: | Q Science > QH Natural history > QH301 Biology Q Science > QH Natural history > QH426 Genetics R Medicine > RM Therapeutics. Pharmacology |
| Divisions: | Pharmacy & Biomolecular Sciences |
| Publisher: | BMJ Publishing Group |
| Related URLs: | |
| Date Deposited: | 22 Sep 2020 11:55 |
| Last Modified: | 04 Sep 2021 06:38 |
| DOI or ID number: | 10.1136/jmedgenet-2015-103576 |
| URI: | https://researchonline.ljmu.ac.uk/id/eprint/13696 |
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