Regions of Homozygocity size patterns among diverse ethnic groups in Israel: Toward tailored diagnostic reporting thresholds.

ABSTRACT

Long contiguous stretches of homozygosity or regions of homozygosity (ROH) are frequently detected via microarray and sequencing technologies. However, consensus on the establishment of specific size cutoffs for reporting ROH remains elusive. This study aims to assess the Total ROH Percentages (TRPS) and size of ROH segments across different ethnic origins, exploring potential disparities and proposing tailored diagnostic thresholds. This retrospective study included 13,035 microarray analyses conducted between 2017 to 2023. ROH segments on autosomal chromosomes were retrieved, and samples lacking ROH segments were excluded. The cohort was categorized based on reported ethnic origins, and TRPS and ROH segment size were analyzed for each origin. Distinct TRPS values were noted among different ethnic groups, ranging from median 0.36% in Ethiopian Jewish cohort and up to 6.42% in the Bedouin population. Wide range of 99th percentiles of ROH segment size for various origins was noted, ranging from 10.6 to 51.5 Mb. A significant correlation between ROH segment sizes and TRPS was noted in each origin. Statistically significant differences in ROH segment sizes were noted between the Jewish and the Israeli Arab/Druze origins in TRPS from 1% to 9.99%, whereas extremities of low (0.11%-0.99%) and high (over 10%) TRPS yielded no significant differences. In conclusion, as fixed absolute size thresholds may overlook pathogenic segments in certain populations while generating excessive reports in others, tailored approaches to define ROH reporting thresholds can be considered to facilitate the accuracy and clinical relevance of genomic analyses.