Angelman syndrome genotypes manifest varying degrees of clinical severity and developmental impairment.

Autor: Keute M; Roche Pharma Research and Early Development, Neuroscience and Rare Diseases, Roche Innovation Center Basel, Basel, Switzerland.; Department of Neurology, Otto-von-Guericke-University, Magdeburg, Germany., Miller MT; Roche Pharma Research and Early Development, Neuroscience and Rare Diseases, Roche Innovation Center Basel, Basel, Switzerland., Krishnan ML; Roche Pharma Research and Early Development, Neuroscience and Rare Diseases, Roche Innovation Center Basel, Basel, Switzerland., Sadhwani A; Department of Psychiatry, Boston Children's Hospital, Boston, MA, USA.; Harvard Medical School, Boston, MA, USA., Chamberlain S; Department of Genetics and Genome Sciences, University of Connecticut, Farmington, CT, USA., Thibert RL; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA., Tan WH; Harvard Medical School, Boston, MA, USA.; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA., Bird LM; Department of Pediatrics, University of California, San Diego, CA, USA.; Department of Genetics/Dysmorphology, Rady Children's Hospital, San Diego, CA, USA., Hipp JF; Roche Pharma Research and Early Development, Neuroscience and Rare Diseases, Roche Innovation Center Basel, Basel, Switzerland. joerg.hipp@roche.com.
Jazyk: angličtina
Zdroj: Molecular psychiatry [Mol Psychiatry] 2021 Jul; Vol. 26 (7), pp. 3625-3633. Date of Electronic Publication: 2020 Aug 13.
DOI: 10.1038/s41380-020-0858-6
Abstrakt: 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.
(© 2020. The Author(s).)
Databáze: MEDLINE
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