Behavioral characterization of dup15q syndrome: Toward meaningful endpoints for clinical trials

Abstract

Duplication of 15q11.2-q13.1 (dup15q syndrome) is one of the most common copy number variations associated with autism spectrum disorders (ASD) and intellectual disability (ID). As with many neurogenetic conditions, accurate behavioral assessment is challenging due to the level of impairment and heterogeneity across individuals. Largescale phenotyping studies are necessary to inform future clinical trials in this and similar ID syndromes. This study assessed developmental and behavioral characteristics in a large cohort of children with dup15q syndrome, and examined differences based on genetic subtype and epilepsy status. Participants included 62 children (2.5-18 years). Across individuals, there was a wide range of abilities. Although adaptive behavior was strongly associated with cognitive ability, adaptive abilities were higher than cognitive scores. Measures of ASD symptoms were associated with cognitive ability, while parent report of challenging behavior was not. Both genetic subtype and epilepsy were related to degree of impairment across cognitive, language, motor, and adaptive domains. Children with isodicentric duplications and epilepsy showed the greatest impairment, while children with interstitial duplications showed the least. On average, participants with epilepsy experienced seizures over 53% of their lives, and half of children with epilepsy had infantile spasms. Parents of children with isodicentric duplications reported more concerns regarding challenging behaviors. Future trials in ID syndromes should employ a flexible set of assessments, allowing each participant to receive assessments that capture their skills. Multiple sources of information should be considered, and the impact of language and cognitive ability should be taken into consideration when interpreting results. K E Y W O R D S behavioral assessment, dup15q syndrome, epilepsy, intellectual disability

Abnormal sleep physiology in children with 15q11.2-13.1 duplication (Dup15q) syndrome

“…Based on direct assessments using the Autism Diagnostic Observation Schedule (ADOS), obtained from a prior study [ 56 ], or on clinical reports of previously conducted assessments, all 15 Dup15q syndrome participants in this study met criteria for ASD. The NT control group included children that were admitted to UCLA for EEG evaluation of paroxysmal events or spells that were ultimately determined to be non-epileptic in the context of normal EEG results.…”

Chromosome 15 syndromes associated with intellectual and developmental disabilities.

“…Cognitive ability. All children with idic (15) and most children with int ( 15) have intellectual impairment, ranging from mild to profound (Ageeli et al, 2014;Battaglia et al, 2010;DiStefano et al, 2016DiStefano et al, , 2019Urraca et al, 2013). Individuals with dup15q syndrome show a generally consistent profile of impairment across domains, with no clear pattern of strengths and weaknesses (DiStefano et al, 2016(DiStefano et al, , 2019.…”

“…Epilepsy is associated with a higher degree of cognitive and language impairment (DiStefano et al, 2016(DiStefano et al, , 2019. Severity of epilepsy also may relate to severity of neurodevelopmental disabilities, as evidenced by the fact that children with a history of infantile spasms have the greatest degree of cognitive impairment (DiStefano et al, 2019).…”

The Cost of Raising Individuals with Fragile X or Chromosome 15 Imprinting Disorders in Australia

“…Approximately 30% of individuals with FXS (Richards et al, 2015), 26.7% with PWS (Bennett et al, 2015), and 34% with AS (Richards et al, 2015) are reported to meet diagnostic criteria for ASD. Compared to other copy number variants known to cause ASD, Dup15q syndrome confers the greatest risk (Moreno- De-Luca et al, 2013), and as such most individuals with Dup15q syndrome meet diagnostic criteria for ASD (DiStefano et al, 2020). Nonetheless, across all four syndromes autistic features are common, regardless of whether these symptoms meet diagnostic thresholds.…”