Chromosome 15 Imprinting Disorders: Genetic Laboratory Methodology and Approaches

Abstract

Chromosome 15 imprinting disorders include Prader-Willi (PWS) and Angelman (AS) syndromes, which are caused by absent expression from the paternal and maternal alleles in the chromosome 15q11. 2-q13 region, respectively. In addition, chromosome 15q duplication caused by the presence of at least one additional maternally derived copy of the 15q11.2-q13 region can lead to seizures, cognitive and behavioral problems. We focus on PWS and AS in the report, and expand the discussion of clinical care and description with genetic testing to include high-resolution studies to more specifically characterize the molecular mechanisms of disease. The importance of early diagnosis with the necessity for accurate molecular characterization through a step-wise algorithm is emphasized in an era of targeted therapeutic interventions. We present a flowchart to aid in ordering specialized genetic testing as several methods are available for patients presenting with features of PWS and/or AS.

Keywords: Angelman syndrome; Prader-Willi syndrome; chromosome 15 disorders; duplication 15q; genetic testing flowchart; imprinting disorders; targeted genetic treatment approaches.

Graphical Abstract

Genetic testing flowchart for patients referred for Prader-Willi syndrome (PWS)/Angelman syndrome (AS). *Rule out Chr15 translocations or inversions by routine chromosome studies; consider other obesity-related genetic disorders; may require fragile X syndrome DNA screening for FMR1 gene repeat expansion or advanced genetic testing with next-generation sequencing (NGS) for FMR1 or other candidate gene variants using whole-exome sequencing (WES) or whole-genome sequencing (WGS; e.g., monogenic causes of obesity). **Can be used to check on methylation status of other Chr15 imprinted genes; ddPCR, droplet digital PCR can be used for mosaicism screening.