Clinical utility of runs of homozygosity in the identification of genetic causes in individuals with rare diseases.

Purpose: To evaluate the clinical utility of runs of homozygosity (ROH) in identifying the genetic causes of rare diseases in our patient population. Methods: All unrelated patients ( Results: A total of 947 patients had at least 1 ROH > 5 Mb, and the majority of these (75%) were recurrent. One of the recurrent ROH, located at 16p11.2p11.1, was significantly increased in our patient population, especially in the Hispanic/Latino and Native Americans, compared with the general population. Approximately 1% (26/2787) of patients had possible uniparental disomy (UPD) and follow-up genetic testing on 2 patients revealed paternal UPD(14) in 1 patient and possible paternal UPD(6) in the other. Deleterious homozygous variants were found in 14 of 78 patients with nonrecurrent ROH who underwent follow-up sequencing studies. Of these 14 patients, causal genes were found to be within the ROH in 12 (15.4%) with causal genes within ROH smaller than 5 Mb in 5 patients, and 4 of these 5 patients were Native Americans. Deleterious homozygous variants were detected in 2 patients without nonrecurrent ROH; however, these were not located within ROH 1 Mb and larger. Conclusion: Our results highlight the importance of investigating ROH 1 Mb and larger for deleterious homozygous variants in patients with nonrecurrent ROH 5 Mb and larger to identify the genetic basis of the presenting features.