Mutations in Linkage Disequilibrium With Putative Disease-Causing Mutations

The statement that “mutations in gene X cause disease Y” is a hypothesis to be tested, not a statement of fact. For inherited diseases such as retinal dystrophies, one substantiating piece of evidence is the presence of a putative disease-causing mutation in more than one family with the same disease. In this issue, Arno et al.¹ provide an instructive example of a possible flaw in this argument: if all affected families share the same mutation, then the mutation may have arisen in a shared, common ancestor and, therefore, another mutation physically close to the hypothetical cause may be the actual cause. A shared mutation arising from a common ancestor is a founder mutation, and variants close to the mutation are in linkage disequilibrium with each other. Even for mutations that arose many generations ago, the region of linkage disequilibrium is hundreds-of-thousands of base pairs in length, encompassing many genes. Arno et al.¹ report next-generation sequencing in families with inherited retinal dystrophies; among the families, six have a homozygous mutation in the RGR gene on chromosome 10q, which codes for an RPE-specific G protein-coupled receptor. The RGR mutation, Ser66Arg, was first reported by Morimura et al.² as the probable cause of disease in one of the families. However, Arno et al.¹ also found a frame shift mutation in a nearby gene, CDHR1, a gene previously associated with recessive rod–cone dystrophy.^3,4 Based on several lines of evidence, the CDHR1 mutation is the probable cause of disease in these families and the RGR mutation is a rare, benign variant in linkage disequilibrium. This brings into question whether mutations in RGR do, in fact, cause recessive retinal disease, and suggests that other one-off mutations may not be pathogenic, in spite of published reports to the contrary.