Genetics of Prader–Willi and Angelman syndromes: 2024 update

Prader-Willi (PWS) and Angelman (AS) syndromes arise from errors in 15q11-q13 imprinting. This review describes recent advances in genomics and how these expand our understanding of these rare disorders, guiding treatment strategies to improve patient outcomes. PWS features include severe infantile hypotonia, failure to thrive, hypogonadism, developmental delay, behavioral and psychiatric features, hyperphagia, and morbid obesity, if unmanaged. AS presents severe intellectual disability, motor dysfunction, seizures, absent speech, and a characteristic happy demeanor. Standard-of-care testing involves SNRPN promoter methylation, chromosomal microarrays and genomic studies for individuals presenting these features. These tests identify syndromic-specific DNA methylation patterns and molecular genetic classes responsible for disease etiology. This review provides an update on studies of genotype-phenotype relationships and novel genomic technologies used for diagnostic purposes. We give an overview and update on the genetics and underlying mechanisms associated with symptoms and potential treatments with focus on features reported to be different between specific molecular genetic classes. The review also describes laboratory testing methods for screening and diagnosis of these imprinting disorders with implications for clinical practice.