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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: BACKGROUND:Children with autism spectrum disorder (ASD) display impressive clinical heterogeneity, also involving treatment response. Genetic variants can contribute to explain this large interindividual phenotypic variability. METHODS:Array-CGH (a-CGH) and whole genome sequencing (WGS) were performed on a multiplex family with two small children diagnosed with ASD at 17 and 18 months of age. Both brothers received the same naturalistic intervention for one year according to the Early Start Denver Model (ESDM), applied by the same therapists, yielding dramatically different treatment outcomes. RESULTS:The older sibling came out of the autism spectrum, while the younger sibling displayed very little, in any, improvement. This boy was subsequently treated applying a structured Early Intensive Behavioral Intervention paired with Augmentative Alternative Communication, which yielded a partial response within another year. The ESDM nonresponsive child carries a novel maternally inherited 65 Kb deletion at chr. 13q32.2 spanning FARP1. Farp1 is a synaptic scaffolding protein, which plays a significant role in neural plasticity. CONCLUSION:These results represent a paradigmatic example of the heuristic potential of genetic markers in predicting treatment response and possibly in supporting the targeted prescription of specific early intervention approaches.

SUBMITTER: Cucinotta F

PROVIDER: S-EPMC7507005 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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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.

Cucinotta Francesca F Ricciardello Arianna A Turriziani Laura L Calabrese Giorgia G Briguglio Marilena M Boncoddo Maria M Bellomo Fabiana F Tomaiuolo Pasquale P Martines Silvia S Bruschetta Marianna M La Fauci Belponer Francesca F Di Bella Tiziana T Colombi Costanza C Baccarin Marco M Picinelli Chiara C Castronovo Paola P Lintas Carla C Sacco Roberto R Biederer Thomas T Kellam Barbara B Scherer Stephen W SW Persico Antonio M AM

Molecular genetics & genomic medicine 20200625 9

<h4>Background</h4>Children with autism spectrum disorder (ASD) display impressive clinical heterogeneity, also involving treatment response. Genetic variants can contribute to explain this large interindividual phenotypic variability.<h4>Methods</h4>Array-CGH (a-CGH) and whole genome sequencing (WGS) were performed on a multiplex family with two small children diagnosed with ASD at 17 and 18 months of age. Both brothers received the same naturalistic intervention for one year according to the E ...[more]

PMID: 32588496

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Project description:OBJECTIVE:To determine the effect of the Early Start Denver Model (ESDM) for treatment of young children with autism on health care service use and costs. METHOD:We used data from a randomized trial that tested the efficacy of the ESDM, which is based on developmental and applied behavioral analytic principles and delivered by trained therapists and parents, for 2 years. Parents were interviewed about their children's service use every 6 months from the onset of the intervention to follow-up (age 6 years). The sample for this study consisted of 39 children with autism who participated in the original randomized trial at age 18 to 30 months, and were also assessed at age 6 years. Of this sample, 21 children were in the ESDM group, and 18 children were in the community care (COM) group. Reported services were categorized and costed by applying unit hourly costs. Annualized service use and costs during the intervention and post intervention for the two study arms were compared. RESULTS:During the intervention, children who received the ESDM had average annualized total health-related costs that were higher by about $14,000 than those of children who received community-based treatment. The higher cost of ESDM was partially offset during the intervention period because children in the ESDM group used less applied behavior analysis (ABA)/early intensive behavioral intervention (EIBI) and speech therapy services than children in the comparison group. In the postintervention period, compared with children who had earlier received treatment as usual in community settings, children in the ESDM group used less ABA/EIBI, occupational/physical therapy, and speech therapy services, resulting in significant cost savings in the amount of about $19,000 per year per child. CONCLUSION:Costs associated with ESDM treatment were fully offset within a few years after the intervention because of reductions in other service use and associated costs. CLINICAL TRIAL REGISTRATION INFORMATION:Early Characteristics of Autism; http://clinicaltrials.gov/; NCT0009415.

Project description:Evidence-based, early intervention significantly improves developmental outcome in young children with autism. Nonetheless, there is high interindividual heterogeneity in developmental trajectories during the therapy. It is established that starting intervention as early as possible results in better developmental outcomes. But except for younger age at start, there is no clear consensus about behavioral characteristics that could provide a reliable individual prediction of a child's developmental outcome after receiving an early intervention. In this study, we analyze developmental trajectories of preschoolers with autism who received 2 years of intervention using the Early Start Denver Model (ESDM) approach in Geneva, Switzerland in an individual setting (n = 55, aged 28.7 ± 5.1 months with a range of 15–42). Our aim was to identify early predictors of response to intervention. We applied a cluster analysis to distinguish between 3 groups based on their cognitive level at intake, and rates of cognitive change over the course of intervention. The first group of children only had a mild cognitive delay at intake and nearly no cognitive delay by the end of intervention (Higher Cognitive at baseline: HC). The children in the two other groups all presented with severe cognitive delay at baseline. However, they had two very different patterns of response to intervention. The majority significantly improved developmental scores over the course of intervention (Optimal Responders: OptR) whereas a minority of children showed only modest improvement (Minimal Responders: MinR). Further analyses showed that children who ended up having an optimal 2-year intervention outcome (OptR) were characterized by higher adaptive functioning at baseline combined with rapid developmental improvement during the first 6 months of intervention. Inversely, less significant progress by the sixth month of intervention was associated with a less optimal response to treatment (MinR).

Project description:ImportanceAutism spectrum disorder (ASD) is a neurodevelopmental disorder associated with different genetic etiologies. Prospective examination of familial-risk infants informs understanding of developmental trajectories preceding ASD diagnosis, potentially improving early detection.ObjectiveTo compare outcomes and trajectories associated with varying familial risk for ASD across the first 3 years of life.Design, setting, and participantsThis longitudinal, prospective cohort study used data from 11 sites in the Baby Siblings Research Consortium database. Data were collected between 2003 and 2015. Infants who were younger siblings of children with ASD were followed up for 3 years. Analyses were conducted in April 2018. Of the initial 1008 infants from the database, 573 were removed owing to missing necessary data, diagnostic discrepancies, or only having 1 older sibling.ExposuresNumber of siblings with ASD.Main outcomes and measuresOutcomes included ASD symptoms, cognitive abilities, and adaptive skills. Diagnosis (ASD or no ASD) was given at 36-month outcome. The no-ASD group was classified as atypical (developmental delays and/or social-communication concerns) or typical for some analyses. Generalized linear mixed models examined developmental trajectories by ASD outcome and familial-risk group.ResultsIn the 435 analyzed participants (age range at outcome, 32-43 months; 246 male [57%]), 355 (82%) were from single-incidence families (1 sibling with ASD and ≥1 sibling without ASD) and 80 (18%) were from multiplex families (≥2 siblings with ASD). There were no significant group differences in major demographics. Children from multiplex families were more likely than those from single-incidence families to be classified as having ASD (29 of 80 [36%] vs 57 of 355 [16%]; 95% CI, 9%-31%; P < .001) and less likely as typical (26 of 80 [33%] vs 201 of 355 [57%]; 95% CI, -36% to -13%; P < .001), with similar rates of atypical classifications (25 of 80 [31%] vs 97 of 355 [27%]; 95% CI, -7% to 15%; P = .49). There were no differences in ASD symptoms between multiplex and single-incidence groups after controlling for ASD outcome (95% CI, -0.02 to 0.20; P = .18). During infancy, differences in cognitive and adaptive abilities were observed based on ASD outcome in the single-incidence group only. At 36 months, the multiplex/no-ASD group had lower cognitive abilities than the single-incidence/no-ASD group (95% CI, -11.89 to -2.20; P = .02), and the multiplex group had lower adaptive abilities than individuals in the single-incidence group after controlling for ASD outcome (95% CI, -9.01 to -1.48; P = .02).Conclusions and relevanceInfants with a multiplex family history of ASD should be monitored early and often and referred for early intervention at the first sign of concern. Direct examination of genetic contributions to neurodevelopmental phenotypes in infants with familial risk for ASD is needed.

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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.

Publications

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

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