Copy number loss upstream of RAI1 uncovers gene expression regulatory region that may impact Potocki–Lupski syndrome diagnosis. Issue 1 (December 2015)

• Record Type: Journal Article
• Authors: Alaimo, Joseph; Mullegama, Sureni; Thomas, Mary; Elsea, Sarah
• Is Part Of: Molecular cytogenetics. Volume 8:Issue 1(2015)
• Page Start: 1
• Page End: 6
• Publication Date: 2015-12
• Subjects: RAI1 -- Structural variation -- Copy number variation -- SMS -- PTLS -- ENCODE; Cytogenetics -- Periodicals; Chromosomes -- Periodicals; Molecular genetics -- Periodicals; 572.805
• DOI: 10.1186/s13039-015-0179-7
• Languages: English
• ISSNs: 1755-8166

Abstract

Abstract The identification of structural variants of uncertain clinical significance is increasing; however, studies delineating the functional consequence of these variants in the pathogenicity of phenotypic features are lacking. Understanding the consequence of structural variants such as copy number alterations and their role in gene expression changes is paramount in order to perform a comprehensive analysis of genetic effects on phenotypic variation and disease.RAI1 is a dosage-sensitive essential neurodevelopmental gene. Copy number loss ofRAI1 results in Smith-Magenis syndrome while copy number gain results in Potocki-Lupski syndrome. Here, we present a case of a six year old female with a newly identified maternally inherited copy number loss that lies within the Smith-Magenis syndrome common deletion region, butRAI1 copy number is normal. Integration of the Encyclopedia of DNA Elements (ENCODE) data at the affected region suggests that the deletion disrupts several cis-acting regulatory elements upstream ofRAI1, such as multiple repressor sites and an insulator region. Gene expression studies revealed that both the proband and the mother have significantly elevatedRAI1 mRNA levels suggesting that the structural variant alters gene expression regulation. The proband and the mother both have some features of Potocki-Lupski syndrome, while the child appears to be more affected with autistic-like features. Overall, our work demonstrates that the integration of ENCODE data with structural variants of uncertain significance aids in delineating a functional consequence to a genomic aberration and subsequent diagnosis.