Germline mutations in RYR1 are associated with foetal akinesia deformation sequence/lethal multiple pterygium syndrome

Introduction: Foetal akinesia deformation sequence syndrome (FADS) is a genetically heterogeneous disorder characterised by the combination of foetal akinesia and developmental defects which may include pterygia (joint webbing). Traditionally multiple pterygium syndrome (MPS) has been divided into two forms: prenatally lethal (LMPS) and non-lethal Escobar type (EVMPS) types. Interestingly, FADS, LMPS and EVMPS may be allelic e.g. each of these phenotypes may result from mutations in the foetal acetylcholine receptor gamma subunit gene (CHRNG). Many cases of FADS and MPS do not have a mutation in a known FADS/ MPS gene and we undertook molecular genetic studies to identify novel causes of these phenotypes. Results: After mapping a novel locus for FADS/ LMPS to chromosome 19, we identified a homozygous null mutation in the RYR1 gene in a consanguineous kindred with recurrent LMPS pregnancies. Resequencing of RYR1 in a cohort of 66 unrelated probands with FADS/LMPS/EVMPS (36 with FADS/ LMPS and 30 with EVMPS) revealed two additional homozygous mutations in frame deletions). The overall frequency of RYR1 mutations in probands with FADS/ LMPS was 8.3%. Conclusions: Our findings report, for the first time, a homozygous RYR1 null mutation and expand the range of RYR1-related phenotypes to include early lethal FADS/ LMPS. We suggest that RYR1 mutation analysis should be performed in cases of severe FADS/ LMPS even in the absence of specific histopathological indicators of RYR1-related disease.