Regions of homozygosity identified by oligonucleotide SNP arrays: evaluating the incidence and clinical utility

Regions of homozygosity identified by oligonucleotide SNP arrays: evaluating the incidence and clinical utility

European Journal of Human Genetics, August 2014

25118026

Jia-Chi Wang, Leslie Ross, Loretta W Mahon, Renius Owen, Morteza Hemmat, Boris T Wang, Mohammed El Naggar, Kimberly A Kopita, Linda M Randolph, John M Chase, Maria J Matas Aguilera, Juan López Siles, Joseph A Church, Natalie Hauser, Joseph J Shen, Marilyn C Jones, Klaas J Wierenga, Zhijie Jiang, Mary Haddadin, Fatih Z Boyar, Arturo Anguiano, Charles M Strom, Trilochan Sahoo

Copy neutral segments with allelic homozygosity, also known as regions of homozygosity (ROHs), are frequently identified in cases interrogated by oligonucleotide single-nucleotide polymorphism (oligo-SNP) microarrays. Presence of ROHs may be because of parental relatedness, chromosomal recombination or rearrangements and provides important clues regarding ancestral homozygosity, consanguinity or uniparental disomy. In this study of 14 574 consecutive cases, 832 (6%) were found to harbor one or more ROHs over 10 Mb, of which 651 cases (78%) had multiple ROHs, likely because of identity by descent (IBD), and 181 cases (22%) with ROHs involving a single chromosome. Parental relatedness was predicted to be first degree or closer in 5%, second in 9% and third in 19%. Of the 181 cases, 19 had ROHs for a whole chromosome revealing uniparental isodisomy (isoUPD). In all, 25 cases had significant ROHs involving a single chromosome; 5 cases were molecularly confirmed to have a mixed iso- and heteroUPD15 and 1 case each with segmental UPD9pat and segmental UPD22mat; 17 cases were suspected to have a mixed iso- and heteroUPD including 2 cases with small supernumerary marker and 2 cases with mosaic trisomy. For chromosome 15, 12 (92%) of 13 molecularly studied cases had either Prader-Willi or Angelman syndrome. Autosomal recessive disorders were confirmed in seven of nine cases from eight families because of the finding of suspected gene within a ROH. This study demonstrates that ROHs are much more frequent than previously recognized and often reflect parental relatedness, ascertain autosomal recessive diseases or unravel UPD in many cases.European Journal of Human Genetics advance online publication, 13 August 2014; doi:10.1038/ejhg.2014.153.