D.P.6 Whole exome sequencing applied to foetal akinesia

Abstract

Foetal akinesia/hypokinesia is an absence or decrease of movement in utero resulting in a spectrum of anomalies characterised by intrauterine growth retardation, contractures, craniofacial anomalies, limb anomalies, pulmonary hypoplasia and polyhydramnios. Despite a large number of disease genes (>30) being associated with this heterogenous group of disorders, the majority of cases are without a genetic diagnosis. The aim of this study was to investigate the use of whole exome sequencing (WES) to identify the causative gene/s in a preliminary set of four families with foetal akinesia. In three families presenting with foetal akinesia and nemaline bodies, all the known nemaline myopathy genes were excluded by WES. The fourth family presented with lethal multiple pterygium syndrome. WES of DNA from two affected sibs revealed compound heterozygous mutations in the glycogen branching enzyme-1 gene (GBE1): a known splice site mutation (c.691+2T>C) and a novel missense mutation (c.956A>G; p.His319Arg) at a highly conserved residue. Each parent carried one of the mutations. GBE1 mutations are known to cause glycogen storage disease IV (GSD IV), a subset of which present with a severe neuromuscular foetal akinesia phenotype. In light of the genetic findings, the muscle pathology was reviewed and PAS positive, diastase resistant faintly refractile material was observed, consistent with GSD IV. Our data highlight that novel nemaline myopathy gene/s remain to be identified and that WES can be used successfully for the diagnosis of foetal akinesias. This study expands the genotype–phenotype correlation of GBE1 mutations: (1) since GSD IV should now be considered in cases presenting as lethal multiple pterygium syndrome and (2) since the vast majority of known foetal akinesia GSD IV cases are due to large indels or frameshift mutations and it is generally considered that the type of the mutations corresponds with clinical severity.