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.
Highlights
Phelan-McDermid syndrome (PMS) is a genetic disorder caused by chromosomal rearrangements of the 22q13.3 region and pathogenic variants in SHANK3 [1, 2]
Except for A4GALT, all candidate genes have been associated with phenotypic traits compatible with the clinical features reported in the cases analyzed (Sheet 3 in S1 File)
Some of the genes were detected in one individual (i.e., TUBGCP6) and others in up to nine individuals (i.e., ADSL), which indicates a heterogeneous contribution of position effects to the overall clinical presentation
Summary
This study aimed to investigate the potential role of position effects on 22q13.3 genes and to assess the overall impact of such effects on the clinical, metabolic, and gene expression variability in PMS. We selected a limited number of samples because we wanted to validate a mechanism, our aim was not to study the expression profile on any available patient with PMS. Our goal was to identify wells in which the levels of NADH generated by PMS cells were significantly different from ones measured in controls
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