ESPE Abstracts (2015) 84 FC4.2

A Recurrent Homozygous NDUFB3 Mutation, p.Trp22Arg Causes a Short Stature Disorder and Mitochondrial Protein Complex I Deficiency with a Variable Metabolic Phenotype

Philip G Murraya,b, Charlottle L Alstonc, Langping Hec, Robert McFarlandc, Julian PH Shieldd,e, Andrew A M Morrisb, Ellen Crushellf, Joanne Hughesf, Robert W Taylorc & Peter E Claytona,b

aUniversity of Manchester, Manchester, UK; bRoyal Manchester Children’s Hospital, Manchester, UK; cNewcastle University, Newcastle, UK; dUniversity of Bristol, Bristol, UK; eBristol Royal Children’s Hospital, Bristol, UK; fTemple Street Children’s University Hospital, Dublin, Ireland

Background: Many children with short stature (defined as height SDS <−2S.D.) have no identified cause for their growth impairment and are classified as either small for gestational age or idiopathic short stature depending on birth size. Whole exome sequencing (WES) is a useful tool to identify new genetic diagnoses in this group. Here we describe a recurrent NDUFB3 mutation in children with intra-uterine growth retardation, short stature and a variable metabolic phenotype.

Patients and methods: Two siblings (one male aged eight birth weight 2.5 kg, one female aged seven birth weight 2.27 kg) presented with short stature and subtle dysmorphism. No diagnosis was reached despite extensive biochemical and genetic investigations. WES of the mother and affected siblings was undertaken.

Results: One variant compatible with autosomal recessive inheritance with a minor allele frequency <1% and predicted to be deleterious by in silico analysis was identified. This missense variant (c.64T>C, p.Trp22Arg) in NDUFB3 (NADH-ubiquinone oxidoreductase 1 beta subcomplex 3, a nuclear encoded component of complex I of the mitochondrial respiratory chain) was previously reported to be associated with a severe neurometabolic phenotype and death in infancy. Sanger sequencing confirmed parents and unaffected siblings were heterozygous and affected siblings homozygous for the mutation. A targeted next generation sequencing strategy identified a further seven patients, from six families, all homozygous for the p.Trp22Arg mutation. They comprise a clinically distinct group with intra-uterine growth retardation, postnatal growth impairment and characteristic facial appearance with frontal bossing, midface hypoplasia and poorly defined philtrum. Intelligence is normal and the metabolic phenotype is variable from no symptoms to life threatening episodes of lactic acidosis and cardiomyopathy in infancy.

Conclusions: Patients with the NDUFB3 p.Trp22Arg mutation may present with pre- and postnatal growth failure with a variable metabolic phenotype where some patients may present only with growth failure and subtle dysmorphism.

Funding: This work was supported by a Society for Endocrinology Early Career Grant.