P.9.14 Next generation sequencing provides diagnosis for multiple foetal akinesia disorders

Abstract

Whole exome sequencing (WES) permits cost effective causative mutation identification in highly heterogeneous diseases. Foetal akinesia/hypokinesia (the absence of or decreased movement in utero) is one disease group where WES is revolutionising patient diagnosis. The aim of this study was to identify the genetic cause of disease in a cohort of patients presenting with foetal akinesia and/or arthrogryposis. The first family in which causative variants were identified consisted of two siblings diagnosed with non-lethal multiple pterygium syndrome. WES of the proband revealed two novel mutations in a recently identified (Jan 2013) disease gene (ECEL1) causing distal arthrogryposis (DA) type 5D; a missense mutation (c.1531G>A; p.Gly511Ser) and a splice site mutation (c.1797-1G>A). Further investigations confirmed that the mutations co-segregated with disease. The clinical features of the siblings are in keeping with the described clinical picture for DA5D. The second family presented with Freeman-Sheldon syndrome (DA2A). WES of this proband revealed a known mutation in MYH3 (c.2015G>A; p.Arg672His). Sanger sequencing suggests the mutation likely arose de novo as neither of the parents carried the mutation. A third family presented with two consecutive pregnancies showing limited foetal movement, polyhydramnios, oedema and camptodactlyly. Muscle biopsy showed occasional cores and minicores. WES of the proband revealed two novel RYR1 variants: c.2455C>T; p.Arg819∗ and c.5989G>A; p.Glu1997Lys, as well as a novel TPM3 variant (c.502C>G; p.Leu168Val). The pathogenic significance of the apparent double trouble is yet to be clarified. This study exemplifies the capabilities of WES in the diagnoses of cases of foetal akinesia and arthrogryposis. It also highlights apparent “double trouble” which is likely to be recognized more as the use of WES becomes more widespread. In many other probands we did not identify causative mutations indicating perhaps the limitations of WES.