Position effects of 22q13 rearrangements on candidate genes in Phelan-McDermid syndrome

PLoS One. 2021 Jul 6;16(7):e0253859. doi: 10.1371/journal.pone.0253859. eCollection 2021.

Abstract

Phelan-McDermid syndrome (PMS) is a multi-system disorder characterized by significant variability in clinical presentation. The genetic etiology is also variable with differing sizes of deletions in the chromosome 22q13 region and types of genetic abnormalities (e.g., terminal or interstitial deletions, translocations, ring chromosomes, or SHANK3 variants). Position effects have been shown to affect gene expression and function and play a role in the clinical presentation of various genetic conditions. This study employed a topologically associating domain (TAD) analysis approach to investigate position effects of chromosomal rearrangements on selected candidate genes mapped to 22q13 in 81 individuals with PMS. Data collected were correlated with clinical information from these individuals and with expression and metabolic profiles of lymphoblastoid cells from selected cases. The data confirmed TAD predictions for genes encompassed in the deletions and the clinical and molecular data indicated clear differences among individuals with different 22q13 deletion sizes. The results of the study indicate a positive correlation between deletion size and phenotype severity in PMS and provide evidence of the contribution of other genes to the clinical variability in this developmental disorder by reduced gene expression and altered metabolomics.

Publication types

  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Child
  • Child, Preschool
  • Chromosome Deletion
  • Chromosome Disorders / genetics*
  • Chromosomes, Human, Pair 22 / genetics
  • Cohort Studies
  • Female
  • Gene Rearrangement*
  • Genetic Variation
  • Humans
  • Male

Supplementary concepts

  • Telomeric 22q13 Monosomy Syndrome

Grants and funding

This study was supported in part by the Greenwood Genetic Center Foundation and the Hope for 22q13 Gala. Additional support was provided by the Clemson University School of Nursing Center for Research on Health Disparities, the Clemson University Open Access Publishing Fund, and Clemson Support for Early Exploration and Development (CU SEED) Grant Program.