Abstract
Angelman Syndrome (AS) is a severe neurodevelopmental disorder due to impaired expression of UBE3A in neurons. There are several genetic mechanisms that impair UBE3A expression, but they differ in how neighboring genes on chromosome 15 at 15q11–q13 are affected. There is evidence that different genetic subtypes present with different clinical severity, but a systematic quantitative investigation is lacking. Here we analyze natural history data on a large sample of individuals with AS (n = 250, 848 assessments), including clinical scales that quantify development of motor, cognitive, and language skills (Bayley Scales of Infant Development, Third Edition; Preschool Language Scale, Fourth Edition), adaptive behavior (Vineland Adaptive Behavioral Scales, Second Edition), and AS-specific symptoms (AS Clinical Severity Scale). We found that clinical severity, as captured by these scales, differs between genetic subtypes: individuals with UBE3A pathogenic variants and imprinting defects (IPD) are less affected than individuals with uniparental paternal disomy (UPD); of those with UBE3A pathogenic variants, individuals with truncating mutations are more impaired than those with missense mutations. Individuals with a deletion that encompasses UBE3A and other genes are most impaired, but in contrast to previous work, we found little evidence for an influence of deletion length (class I vs. II) on severity of manifestations. The results of this systematic analysis highlight the relevance of genomic regions beyond UBE3A as contributing factors in the AS phenotype, and provide important information for the development of new therapies for AS. More generally, this work exemplifies how increasing genetic irregularities are reflected in clinical severity.
Highlights
Angelman syndrome (AS) is a rare genetic neurodevelopmental disorder with a prevalence of 1 in 10,000–24,000
Using the largest clinical dataset to date, we confirm previous evidence and clinical intuition that individuals with deletion AS are more impaired than non-deletion AS
This is genetically plausible because deletions include additional genes that likely have an impact on development and brain function
Summary
Angelman syndrome (AS) is a rare genetic neurodevelopmental disorder with a prevalence of 1 in 10,000–24,000. Individuals with UPD have two paternal copies of the chromosome 15q11–q13 segment and two silenced copies of UBE3A, resulting in a near-complete lack of expression in neurons. Imprinting center defects (IPDs) can result from epigenetic events (~85%) or deletions within the AS imprinting center (~15%) and effectively cause the maternal chromosome 15q11q13 region to “behave” like the paternal copy. Differences in clinical features and disease severity between AS genotypes To our knowledge, nine previous studies have characterized the developmental and clinical differences between AS genotypes (summarized in Supplementary Table 1) Taken together, these studies consistently show a more severe clinical phenotype for AS individuals with a deletion compared with those without a deletion, and some suggest that larger deletions lead to more severe impairment than smaller deletions. Using a statistical modeling approach and the largest sample of individuals with AS studied so far, we systematically investigated differences between AS genotypes for several cognitive and developmental domains, with a focus on standardized psychometric developmental tests and questionnaires
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