FARP‐1 deletion is associated with lack of response to autism treatment by early start denver model in a multiplex family

Cucinotta, Francesca; Ricciardello, Arianna; Turriziani, Laura; Calabrese, Giorgia; Briguglio, Marilena; Boncoddo, Maria; Bellomo, Fabiana; Tomaiuolo, Pasquale; Martines, Silvia; Bruschetta, Marianna; Belponer, Francesca La Fauci; Bella, Tiziana Di; Colombi, Costanza; Baccarin, Marco; Picinelli, Chiara; Castronovo, Paola; Lintas, Carla; Sacco, Roberto; Biederer, Thomas; Kellam, Barbara; Scherer, Stephen W.; Persico, Antonio M.

doi:10.1002/mgg3.1373

Cited by 10 publications

(10 citation statements)

References 22 publications

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“…Even the prescription of psychotherapy may benefit in some cases from genetic information, in reference both to indication (par. 2 here) and possibly to treatment of choice [47].…”

Section: Discussionmentioning

confidence: 93%

Actionable Genomics in Clinical Practice: Paradigmatic Case Reports of Clinical and Therapeutic Strategies Based upon Genetic Testing

Butler

Moreno‐De‐Luca

Persico

2022

Genes

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In clinical settings, the information provided by genetic testing can explain the triggers and processes underlying clinical presentations, such as neurodevelopmental disorders, in up to one third of affected individuals. However, translating this knowledge into better and more personalized clinical management to many appears a distant target. This article presents three paradigmatic cases to exemplify how this translational effort can, at least in some instances, be undertaken today with very positive results: (a) a young girl carrying a chr. 16p11.2 duplication can be screened using targeted exams and undertake therapeutic/preventive interventions related to her genetic diagnosis; (b) a 13-year-old boy with intellectual disability and autism spectrum disorder carries a chr. 11q14.1 deletion, partly spanning the DLG2 gene important for synaptic function, and gained over 20 I.Q. points ostensibly due to carbolithium, prescribed in the absence of affective symptoms, exclusively following the pathophysiology pointed out by the genetic results; (c) a 58-year-old woman carries a COL3A1 gene variant responsible for the vascular form of Ehler–Danlos syndrome with colon rupture. Detection of this variant in six members of her extended family allows for better clinical management of the proband and targeted genetic counselling for family members at risk of this connective tissue disorder. The unprecedented flow of genetic information available today through new technologies, if interpreted in the light of current knowledge in clinical diagnosis and care of those with connective tissue disorders and neurodevelopmental disturbances, in biology and in neuropsychopharmacology, can promote better clinical and pharmacological treatment, disease surveillance, and management provided and incorporated into the clinical setting.

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“…Even the prescription of psychotherapy may benefit in some cases from genetic information, in reference both to indication (par. 2 here) and possibly to treatment of choice [47].…”

Section: Discussionmentioning

confidence: 93%

Actionable Genomics in Clinical Practice: Paradigmatic Case Reports of Clinical and Therapeutic Strategies Based upon Genetic Testing

Butler

Moreno‐De‐Luca

Persico

2022

Genes

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“…One of the ultimate aims of autism research is to allow for clinicians to define “which treatment for which child” beforehand, based on clinical predictors and objective biomarkers (genetics, brain imaging, electrophysiology, eye tracking, etc.). This aim not only regards pharmacological therapy [ 7 , 8 ], but also behavioral interventions which, although sharing some common elements, differ significantly in multiple aspects of their methodology. Structured behavioral approaches tend to favor a “teaching” relationship, and employ tasks which preferentially request and strengthen cognitive skills, making broader use of extrinsic motivators [ 9 ]; naturalistic approaches employ a “playground-like” relationship, employing activities that leave greater freedom of choice to the child and act as intrinsic motivators, while primarily requiring and strengthening social cognition (eye contact, theory of mind, joint attention, empathy, etc.).…”

Section: Discussionmentioning

confidence: 99%

“…For many patients, also gene–environment interactions involving a genetic predisposition and prenatal–early-postnatal environmental influences are also plausible [ 6 ]. In addition to diagnosis, genetic variants can also contribute to explain interindividual variability in clinical phenotype, developmental trajectories, and responsiveness to behavioral or pharmacological treatment [ 7 , 8 ]. Hence, heterogeneity at the pathogenetic level translates into great clinical and treatment-related interindividual differences.…”

Section: Introductionmentioning

confidence: 99%

Differential Predictors of Response to Early Start Denver Model vs. Early Intensive Behavioral Intervention in Young Children with Autism Spectrum Disorder: A Systematic Review and Meta-Analysis

Asta

Persico

2022

Brain Sciences

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The effectiveness of early intensive interventions for Autism Spectrum Disorder (ASD) is now well-established, but there continues to be great interindividual variability in treatment response. The purpose of this systematic review is to identify putative predictors of response to two different approaches in behavioral treatment: Early Intensive Behavioral Interventions (EIBI) and the Early Start Denver Model (ESDM). Both are based upon the foundations of Applied Behavioral Analysis (ABA), but the former is more structured and therapist-driven, while the latter is more naturalistic and child-driven. Four databases (EmBase, PubMed, Scopus and WebOfScience) were systematically screened, and an additional search was conducted in the reference lists of relevant articles. Studies were selected if participants were children with ASD aged 12–48 months at intake, receiving either EIBI or ESDM treatment. For each putative predictor, p-values from different studies were combined using Fisher’s method. Thirteen studies reporting on EIBI and eleven on ESDM met the inclusion criteria. A higher IQ at intake represents the strongest predictor of positive response to EIBI, while a set of social cognitive skills, including intention to communicate, receptive and expressive language, and attention to faces, most consistently predict response to ESDM. Although more research will be necessary to reach definitive conclusions, these findings begin to shed some light on patient characteristics that are predictive of preferential response to EIBI and ESDM, and may provide clinically useful information to begin personalizing treatment.

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“…There is minimal knowledge of whether genetic information can guide clinicians to individualize intervention decisions. A few case studies (Cucinotta et al, 2020;Pini et al, 2014;Serret et al, 2015) and our earlier reports indicate a potential to identify an association between an intervention outcome and genetic information Tammimies et al, 2019). Despite large-scale exome sequencing studies in ASD, no studies have directly connected ASDrelated rare sequence variants to intervention outcomes.…”

Section: Most Of the Current Interventions Yield Variable Responses A...mentioning

confidence: 91%

Rare variants in the outcome of social skills group training for autism

Olsson

Becker

et al. 2021

Autism Research

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Exome sequencing has been proposed as the first-tier genetic testing in autism spectrum disorder (ASD). Here, we performed exome sequencing in autistic individuals with average to high intellectual abilities (N = 207) to identify molecular diagnoses and genetic modifiers of intervention outcomes of social skills group training (SSGT) or standard care. We prioritized variants of clinical significance (VCS), variants of uncertain significance (VUS) and generated a pilot scheme to calculate genetic scores of rare and common variants in ASD-related gene pathways. Mixed linear models were used to test the association between the carrier status of VCS/VUS or the genetic scores with intervention outcomes measured by the social responsiveness scale. Additionally, we combined behavioral and genetic features using a machine learning (ML) model to predict the individual response. We showed a rate of 4.4% and 11.3% of VCS and VUS in the cohort, respectively. Individuals with VCS or VUS had improved significantly less after standard care than non-carriers at post-intervention (β = 9.35; p = 0.036), while no such association was observed for SSGT (β = À2.50; p = 0.65). Higher rare variant genetic scores for synaptic transmission and regulation of transcription from RNA polymerase II were separately associated with less beneficial (β = 8.30, p = 0.0044) or more beneficial (β = À6.79, p = 0.014) effects after SSGT compared with standard care at follow-up, respectively. Our ML model showed the importance of rare variants for outcome prediction. Further studies are needed to understand genetic predisposition to intervention outcomes in ASD. Lay SummarySocial skills group training is one of the most common behavior interventions aiming at autistic children and adolescents, but the outcome varies between Sven Bölte and Kristiina Tammimies contributed equally to this study.

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FARP‐1 deletion is associated with lack of response to autism treatment by early start denver model in a multiplex family

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 10 publications

References 22 publications

Actionable Genomics in Clinical Practice: Paradigmatic Case Reports of Clinical and Therapeutic Strategies Based upon Genetic Testing

Actionable Genomics in Clinical Practice: Paradigmatic Case Reports of Clinical and Therapeutic Strategies Based upon Genetic Testing

Differential Predictors of Response to Early Start Denver Model vs. Early Intensive Behavioral Intervention in Young Children with Autism Spectrum Disorder: A Systematic Review and Meta-Analysis

Rare variants in the outcome of social skills group training for autism

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