Cognitive, adaptive and behavioral profile in Sotos syndrome children with 5q35 microdeletion or intragenic variants

Abstract

Sotos syndrome (SoS) is a congenital overgrowth syndrome with variable degree of intellectual disability caused in the 90% of cases by pathogenetic variants of the Nuclear receptor binding SET Domain protein1 (NSD1) gene. NSD1 gene functions can be abrogated by different genetic alterations (i.e., small intragenic pathogenic variants like deletions/insertions, nonsense/missense pathogenic variants, partial gene deletions and whole deletions or microdeletion of 5q35 chromosomal region). Therefore, correlation of the genotype-phenotype with a possible contribution of more implicated genes to the medical, cognitive and behavioral profile is a topic of great interest. Although a more severe learning disability has been described in individuals with 5q35 microdeletion when compared to individuals with NSD1 intragenic pathogenic variants a fully delineated cognitive and behavioral phenotype has not been described yet. The importance of providing clinical characterization in relation to the genotype comes from the necessity to early identify children more at risk of developing psychopathological disorders. We characterize the cognitive, adaptive and behavioral phenotype of a pediatric sample of 64 individuals affected by SoS, performing a standardized neuropsychological evaluation. Secondly, we compare cognitive-behavioral profiles of SoS individuals carrying and not carrying the 5q35 microdeletion. SoS participants were characterized by a mild cognitive impairment of both Intellectual Quotient and adaptive skills in association to borderline symptoms of attention deficit. Our results suggest that the 5q35 microdeletion is associated with lower scores specifically concerning the cognitive, adaptive functioning and behavioral domains. However, longitudinal studies are necessary to confirm these findings and delineate a developmental trajectory of SoS.

A longitudinal characterization of the adaptive and behavioral profile in Sotos syndrome

“…Adverse behavior is rated by parents on a 3 points Likert Scale (0 = not true, 1 = sometimes true, 2 = often true), with higher scores reflecting more problematic child's behavior. According to the T score, a behavior is considered as typical (T < 65), borderline (65-69), or significantly atypical (T > 70).For this study, in line with our previous study(Siracusano et al, 2023), only the three main subscales have been taken into consideration: Internalizing, Externalizing Symptoms, and Total Behavior score.2.5 | Conners' parents rating scale-long form (CPRS-R:L) The Conners' Parent Rating Scale-Revised (CPRS-R:L) (Conners et al, 1998) is a parent-report measure evaluating behavioral difficulties. The CPRS Long Form includes 80 items grouped into seven subscales (Cognitive Problems, Oppositional, Hyperactivity-Impulsivity, Anxious-Shy, Perfectionism, Social Problems, and Psychosomatic).…”

“…All previously enrolled participants-who still continue to be assisted by our Unit-were asked, over the years, to undergo a second evaluation to depict their clinical evolution, by longitudinally characterizing their adaptive skills and behavioral features (internalizing, externalizing symptoms). For the purpose of the present study, we considered the evaluation performed during our previous work (Siracusano et al, 2023) as the baseline assessment (T0); whereas the follow-up assessment provided at distance represents the T1 (Figure 1). At T0 and T1, detailed information concerning intervention (type, duration, frequency) was collected via a parental interview.…”

“…The baseline evaluation (Siracusano et al, 2023) included a standardized assessment of cognitive skills (Intellectual Quotient-IQ), adaptive functioning, and behavioral issues (internalizing, externalizing symptoms) through the below reported instruments.…”

“…Two forms are available depending on the child's age: the "18 months-5 years" and the "6-18 years" form. For this study, we considered for the analyses only the score domains which were statistically significant in our previous project (Siracusano et al, 2023), that is, Cognitive Problems, Inattention score, ADHD Index, Conners_CGI Total score.…”

“…A SoS‐specific cognitive and behavioral profile is still under definition, but a wide range of intellectual functioning and behavioral problems (internalizing: anxiety, withdrawn; externalizing: hyperactivity, disattention) seems to depict a common phenotype of this syndrome (Lane et al, 2016, 2017, 2018, 2019; Siracusano et al, 2023). Particularly, a genotype–phenotype correlation, which includes cognitive and behavioral skills, has not been clearly defined yet (de Boer et al, 2006; Novara et al, 2014; Tatton‐Brown et al, 2005).…”