September 2016
Volume 57, Issue 11
Open Access
Research Highlight  |   September 2016
Mutations in Linkage Disequilibrium With Putative Disease-Causing Mutations
Author Affiliations
  • Stephen P. Daiger
    University of Texas Health Science Center Human Genetics Center, School of Public Health, Houston, Texas, United States;
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 4814. doi:
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      Stephen P. Daiger; Mutations in Linkage Disequilibrium With Putative Disease-Causing Mutations. Invest. Ophthalmol. Vis. Sci. 2016;57(11):4814.

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      © ARVO (1962-2015); The Authors (2016-present)

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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. 
Arno G, Hull S, Carss K, et al. Reevaluation of the retinal dystrophy due to recessive alleles of RGR with the discovery of a cis-acting mutation in CDHR1. Invest Ophthalmol Vis Sci. 2016.
Morimura G, Saindelle-Ribeaudeau F, Berson EL, Dryja TP. Mutations in RGR, encoding a light-sensitive opsin homologue, in patients with retinitis pigmentosa. Nat Genet. 1999; 23: 393–394.
Henderson RH, Li Z, El Aziz MMA, et al. Biallelic mutation of protocadherin-21 (PCDH21) causes retinal degeneration in humans. Mol Vis. 2010; 16: 46–52.
Ostergaard E, Batbayli M, Duno M, Vilhelmsen K, Rosenberg T. Mutations in PCDH21 cause autosomal recessive cone-rod dystrophy. J Med Genet. 2010; 47: 665–669.

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