Intra-familial variability associated with recessive RYR1 mutation diagnosed prenatally by exome sequencing

Objective To determine the underlying molecular aetiology in a non-consanguineous Irish family who have had three fetal losses because of a primary myopathy characterised by fetal akinesia, arthrogryposis multiplex, bilateral pulmonary hypoplasia and reduced muscle bulk. Methods Fetal DNA extracted from amniotic cells was whole genome amplified and subjected to whole exome sequencing. Results Whole exome sequencing identified compound heterozygous variants in RYR1 as the cause of the lethal myopathy in this family. All three fetuses were compound heterozygous for a paternally inherited missense variant (c.2113G>A; p.Gly705Arg) and a novel maternally inherited truncating frameshift deletion (c.8843delC; p.Ser2948Cysfs*58). This family did not have the classic cores and fibre type disproportion typically associated with RYR1 mutation. The RYR1 exome finding was made during the couple's third pregnancy and enabled prenatal genetic testing to be undertaken. Conclusion We show that recessive RYR1 mutations can be associated with significant intra-familial variability in clinical presentation which can complicate prediction of clinical outcome. RYR1 mutations can also cause diverse muscle pathologies which thwarts diagnosis. This study demonstrates the impact that exome-based diagnoses can have for families with lethal disorders. (C) 2016 John Wiley & Sons, Ltd.