American College of Medical Genetics and Genomics: standards and guidelines for documenting suspected consanguinity as an incidental finding of genomic testing

Runs of homozygosity and parental relatedness

“…We wish to discuss new findings on runs of homozygosity (ROH) that could improve upon these recommended guidelines, thereby reducing the occurrence of false-positive and false-negative suggestions of parental relatedness on the basis of genomic testing. Rehder et al 1 recommended that the proportion of an individual genome located in homozygous segments whose lengths exceed a fixed threshold of 2-5 Mb can be compared with textbook autozygosity levels to suggest the level of relationship for the sampled individual. As recognized by Rehder et al 1 and noted in studies of ROH features, 2,3 production of ROH is affected by forces acting on multiple time scales, including not only recent parental relatedness but also parental relatedness within a population at a level generally too distant for the parents to know of the relationship ("background relatedness"), and chance pairing of ancient haplotypes that have been magnified in frequency by founder events and subsequent population expansions.…”

“…Rehder et al 1 recommended that the proportion of an individual genome located in homozygous segments whose lengths exceed a fixed threshold of 2-5 Mb can be compared with textbook autozygosity levels to suggest the level of relationship for the sampled individual. As recognized by Rehder et al 1 and noted in studies of ROH features, 2,3 production of ROH is affected by forces acting on multiple time scales, including not only recent parental relatedness but also parental relatedness within a population at a level generally too distant for the parents to know of the relationship ("background relatedness"), and chance pairing of ancient haplotypes that have been magnified in frequency by founder events and subsequent population expansions. Recent parental relatedness, background relatedness, and founder events contribute primarily to ROH with long, intermediate, and short sizes, respectively, and in this context, the choice by Rehder et al 1 to only consider ROH longer than a fixed threshold is an effort to identify only those ROH arising from recent parental relatedness.…”

“…As recognized by Rehder et al 1 and noted in studies of ROH features, 2,3 production of ROH is affected by forces acting on multiple time scales, including not only recent parental relatedness but also parental relatedness within a population at a level generally too distant for the parents to know of the relationship ("background relatedness"), and chance pairing of ancient haplotypes that have been magnified in frequency by founder events and subsequent population expansions. Recent parental relatedness, background relatedness, and founder events contribute primarily to ROH with long, intermediate, and short sizes, respectively, and in this context, the choice by Rehder et al 1 to only consider ROH longer than a fixed threshold is an effort to identify only those ROH arising from recent parental relatedness. In relation to other studies that focused on a 1.5-Mb threshold, 2 the 2-to 5-Mb threshold level suggested by Rehder et al 1 is comparable but more stringent.…”

“…Townsend et al 1 also raised the point that the working group did not seek input from consumers (patients). This possibility was considered, but it was difficult to know who actually speaks for the general public on this issue.…”

“…We ultimately decided to begin the discussion with input from scientific and medical experts, realizing that the recommendations would serve as a reference point for many perspectives. Townsend et al 1 suggest that the recommendations be withdrawn and revised. I do not believe that they should be withdrawn, but as we stated in the report, I anticipate that they will be refined and revised in response to additional input and evidence.…”