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 (N = 2787), presenting with neurodevelopmental disorders and/or congenital anomalies, who underwent chromosomal microarray testing in our laboratory between July 2019 and December 2023, and publicly available single-nucleotide polymorphism microarray data from 3488 unrelated individuals in the general population were included in this study. Electronic medical records of all 2787 patients were reviewed to obtain information on follow-up genetic testing to identify the genetic causes. 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.