SIDS associated RYR2 p.Arg2267His variant may lack pathogenicity

Sudden infant death syndrome (SIDS) is the sudden death of an infant under 1 year of age that remains unexplained after death scene and medicolegal investigation, including a complete autopsy and clinical history review. The fatal event typically occurs during sleep and heart rhythm during the event is rarely documented. Large series which have utilized molecular autopsy show that long QT syndrome (LQTS) associated cardiac channel mutations contribute to between 5 and 10% of SIDS deaths. In addition, rare novel RYR2 variants have been identified in SIDS victims. Given the lack of a phenotype, the pathogenicity of these variants is inferred from in vitro studies. We report a family with 5 members (mother and 4 children) who are carriers of a rare RYR2 variant (c.6800G > A, p.Arg2267His [Exon: 45], heterozygous) which has previously been identified in a SIDS victim and shown to confer a gain-of-function CPVT phenotype in vitro. All of these 5 family members including the mother (age range 7 to 41 years) have had negative exercise stress tests, echocardiograms and Holter monitors. These findings suggest that caution should be exercised in inferring pathogenicity of rare RYR2 variants based on in vitro functional data which does not always translate to human phenotype.