Pericentromeric regions of homozygosity on the X chromosome: Another likely benign population variant

Elizabeth S Barrie; Yu Li; Devon Lamb-Thrush; Sayaka Hashimoto; Theodora Matthews; Danielle Mouhlas; Robert Pyatt; Shalini C Reshmi; Julie M Gastier-Foster; Ruthann Pfau; Caroline Astbury

doi:10.1016/j.ejmg.2018.02.008

Pericentromeric regions of homozygosity on the X chromosome: Another likely benign population variant

Eur J Med Genet. 2018 Jul;61(7):416-420. doi: 10.1016/j.ejmg.2018.02.008. Epub 2018 Mar 20.

Affiliations

¹ The Institute for Genomic Medicine at Nationwide Children's Hospital, Columbus, OH, USA.
² The Institute for Genomic Medicine at Nationwide Children's Hospital, Columbus, OH, USA; The Ohio State University College of Medicine, Department of Pediatrics, Columbus, OH, USA.
³ The Institute for Genomic Medicine at Nationwide Children's Hospital, Columbus, OH, USA; The Ohio State University College of Medicine, Department of Pathology, Columbus, OH, USA.
⁴ The Institute for Genomic Medicine at Nationwide Children's Hospital, Columbus, OH, USA; The Ohio State University College of Medicine, Department of Pediatrics, Columbus, OH, USA; The Ohio State University College of Medicine, Department of Pathology, Columbus, OH, USA.
⁵ The Institute for Genomic Medicine at Nationwide Children's Hospital, Columbus, OH, USA; The Ohio State University College of Medicine, Department of Pathology, Columbus, OH, USA. Electronic address: astburc@ccf.org.

PMID: 29572065
DOI: 10.1016/j.ejmg.2018.02.008

Abstract

Purpose: While chromosomal regions of homozygosity (ROH) may implicate genes in known recessive disorders, their correlation to disease pathogenicity remains unclear. ROH around the centromere of the X chromosome (pericentromeric, pROH) is regarded as benign, although this has not been empirically demonstrated.

Methods: We examined microarray results from 122 female individuals harboring ROH bordering the X centromere.

Results: Consecutive ROH was most frequently observed for regions Xp11.23 to Xp11.21 and Xq11.1 to Xq12, with an average total size of 16.5 Mb. X chromosome pROH was unlikely related to phenotype in 41% (50/122) of cases due to other explanations: likely pathogenic deletion/duplication (17%, 21/122), apparently unaffected female (7%, 8/122), other clinical explanation (7%, 9/122), or consanguinity (10%, 12/122). Of the remaining cases with pROH as the only finding, four genes were associated with recessive disorders that overlapped one or more clinical features reported in our probands (KDM5C, FGD1, ZC4H2, and LAS1L). X chromosome pROH observed in our cohort overlapped with previously reported regions.

Conclusions: pROH on the X chromosome are commonly observed in both affected individuals with alternate causes of disease as well as in unaffected individuals, suggesting that X chromosome pROH has no clinically significant effect on phenotype.

Keywords: Benign variation; Clinical genetics; Long contiguous stretches of homozygosity; Pericentromeric regions of homozygosity; Runs of homozygosity; SNP microarray; X chromosome.

MeSH terms

Centromere
Chromosomes, Human, X / genetics*
Female
Genetic Variation
Homozygote*
Humans
Phenotype