Autism Heterogeneity in a Densely Sampled U.S. Population: Results From the First 1,000 Participants in the RI-CART Study.

The objective of this study was to establish a large, densely sampled, U.S. population-based cohort of people with autism spectrum disorder (ASD). The Rhode Island Consortium for Autism Research and Treatment (RI-CART) represents a unique public-private-academic collaboration involving all major points of service for families in Rhode Island affected by ASD. Diagnosis was based on direct behavioral observation via the Autism Diagnostic Observation Schedule, Second Edition. For the first 1,000 participants, ages ranged from 21 months to 64 years. Using Geographic Information System and published prevalence rates, the overall cohort is estimated to represent between 20% and 49% of pediatric age persons in Rhode Island with ASD, with demographics representative of U.S. Census. We observed a high rate of co-occurring medical and psychiatric conditions in affected individuals. Among the most prominent findings of immediate clinical importance, we found that females received a first diagnosis of ASD at a later age than males, potentially due to more advanced language abilities in females with ASD. In summary, this is the first analysis of a large, population-based U.S. cohort with ASD. Given the depth of sampling, the RI-CART study reflects an important new resource for studying ASD in a representative U.S. population. Psychiatric and medical comorbidities in ASD constitute a substantial burden and warrant adequate attention as part of overall treatment. Our study also suggests that new strategies for earlier diagnosis of ASD in females may be warranted. Autism Res 2020, 13: 474-488. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: The Rhode Island Consortium for Autism Research and Treatment (RI-CART) represents a unique public-private-academic collaboration involving all major points of service for families in Rhode Island affected by autism spectrum disorder (ASD). In this article, we provide results from the first 1,000 participants, estimated to represent >20% of affected families in the state. Importantly, we find a later age at first diagnosis of ASD in females, which potentially calls attention to the need for improved early diagnosis in girls. Also, we report a high rate of co-occurring medical and psychiatric conditions in affected individuals.

Cognitive and adaptive correlates of an ADOS-derived joint attention composite.

Joint attention skills have been shown to predict language outcomes in children with autism spectrum disorder (ASD). Less is known about the relationship between joint attention (JA) abilities in children with ASD and cognitive and adaptive abilities. In the current study, a subset of items from the Autism Diagnostic Observation Schedule (ADOS), designed to quantify JA abilities, were used to investigate social attention among an unusually large cross-sectional sample of children with ASD (n = 1061). An examination of the association between JA and a range of functional correlates (cognitive and adaptive) revealed JA was significantly related to verbal (VIQ) and non-verbal (NVIQ) cognitive ability as well as all domains of adaptive functioning (socialization, communication, and daily living skills). Additional analyses examined the degree to which the relation between adaptive abilities (socialization, communication, and daily living skills) and JA was maintained after taking into account the potentially mediating role of verbal and nonverbal cognitive ability. Results revealed that VIQ fully mediated the relation between JA and adaptive functioning, whereas the relation between these adaptive variables and JA was only partially mediated by NVIQ. Moderation analyses were also conducted to examine how verbal and non-verbal cognitive ability and gender impacted the relation between JA and adaptive functioning. In line with research showing a relation between language and JA, this indicates that while JA is significantly related to functional outcomes, this appears to be mediated specifically through a verbal cognitive pathway.

Executive function in probands with autism with average IQ and their unaffected first-degree relatives.

OBJECTIVE: This study aimed to characterize executive function (EF) in pedigrees of children with autism spectrum disorder (ASD) and average IQ. The authors examined the hypothesis that deficits in EF relate to lower levels of adaptive functioning, and they assessed evidence for a cognitive extended phenotype in unaffected relatives in a large, well-characterized sample. METHOD: Proband EF was assessed by parent-report questionnaires (Behavior Rating Inventory of Executive Functioning [BRIEF], n = 109) and child neuropsychological tests (Delis-Kaplan Executive Functioning System [D-KEFS], n = 35). EF also was examined in parents (D-KEFS, n = 335) and unaffected siblings (BRIEF, n = 114; D-KEFS, n = 57). Adaptive functioning was assessed by the Vineland Adaptive Behavior Scales-II (n = 155). All data were obtained from the Autism Consortium Clinical Genetics Database. RESULTS: Individuals with ASD showed important EF weaknesses. Multiple regression analyses showed that parent-reported EF deficits were related to profound decreases in adaptive functioning even after controlling for age, IQ, and severity of ASD symptoms. Parent-reported EF also was related to adaptive skills in preschoolers. First-degree unaffected relatives did not demonstrate difficulties with EF compared with normative data. CONCLUSION: In this study, EF impairments do not appear to relate to broad familial risk factors for ASD but may be associated with factors relevant to the expression of ASD in probands. Results support the benefits of EF assessment as a way to identify potential therapeutic targets that could lead to improved adaptive behavior in children with ASD and average IQ.

Genetic and phenotypic diversity of NHE6 mutations in Christianson syndrome.

OBJECTIVE: Recently, Christianson syndrome (CS) has been determined to be caused by mutations in the X-linked Na(+) /H(+) exchanger 6 (NHE6). We aimed to determine the diagnostic criteria and mutational spectrum for CS. METHODS: Twelve independent pedigrees (14 boys, age = 4-19 years) with mutations in NHE6 were administered standardized research assessments, and mutations were characterized. RESULTS: The mutational spectrum was composed of 9 single nucleotide variants, 2 indels, and 1 copy number variation deletion. All mutations were protein-truncating or splicing mutations. We identified 2 recurrent mutations (c.1498 c>t, p.R500X; and c.1710 g>a, p.W570X). Otherwise, all mutations were unique. In our study, 7 of 12 mutations (58%) were de novo, in contrast to prior literature wherein mutations were largely inherited. We also report prominent neurological, medical, and behavioral symptoms. All CS participants were nonverbal and had intellectual disability, epilepsy, and ataxia. Many had prior diagnoses of autism and/or Angelman syndrome. Other neurologic symptoms included eye movement abnormalities (79%), postnatal microcephaly (92%), and magnetic resonance imaging evidence of cerebellar atrophy (33%). Regression was noted in 50%, with recurrent presentations involving loss of words and/or the ability to walk. Medical symptoms, particularly gastrointestinal symptoms, were common. Height and body mass index measures were below normal ranges in most participants. Behavioral symptoms included hyperkinetic behavior (100%), and a majority exhibited high pain threshold. INTERPRETATION: This is the largest cohort of independent CS pedigrees reported. We propose diagnostic criteria for CS. CS represents a novel neurogenetic disorder with general relevance to autism, intellectual disability, Angelman syndrome, epilepsy, and regression.

Clinical characteristics of children with autism spectrum disorder and co-occurring epilepsy.

OBJECTIVES: To estimate the prevalence of epilepsy in children with Autism Spectrum Disorder (ASD) and to determine the demographic and clinical characteristics of children with ASD and epilepsy in a large patient population. METHODS: Cross-sectional study using four samples of children with ASD for a total of 5,815 participants with ASD. The prevalence of epilepsy was estimated from a population-based sample. Children with and without epilepsy were compared on demographic and clinical characteristics. Multivariate logistic regression was used to examine the association between demographic and clinical characteristics and epilepsy. RESULTS: The average prevalence of epilepsy in children with ASD 2-17 years was 12.5%; among children aged 13 years and older, 26% had epilepsy. Epilepsy was associated with older age, lower cognitive ability, poorer adaptive and language functioning, a history of developmental regression and more severe ASD symptoms. The association between epilepsy and the majority of these characteristics appears to be driven by the lower IQ of participants with epilepsy. In a multivariate regression model, only age and cognitive ability were independently associated with epilepsy. Children age 10 or older had 2.35 times the odds of being diagnosed with epilepsy (p<.001) and for a one standard deviation increase in IQ, the odds of having epilepsy decreased by 47% (p<.001). CONCLUSION: This is among the largest studies to date of patients with ASD and co-occurring epilepsy. Based on a representative sample of children with ASD, the average prevalence of epilepsy is approximately 12% and reaches 26% by adolescence. Independent associations were found between epilepsy and older age and lower cognitive ability. Other risk factors, such as poor language and developmental regression, are not associated with epilepsy after controlling for IQ. These findings can help guide prognosis and alert clinicians to patients with ASD who are at increased risk for epilepsy.