Vanessa Hus Bal

Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci

Analysis of de novo CNVs (dnCNVs) from the full Simons Simplex Collection (SSC) (N = 2,591 families) replicates prior findings of strong association with autism spectrum disorders (ASDs) and confirms six risk loci (1q21.1, 3q29, 7q11.23, 16p11.2, 15q11.2-13, and 22q11.2). The addition of published CNV data from the Autism Genome Project (AGP) and exome sequencing data from the SSC and the Autism Sequencing Consortium (ASC) shows that genes within small de novo deletions, but not within large dnCNVs, significantly overlap the high-effect risk genes identified by sequencing. Alternatively, large dnCNVs are found likely to contain multiple modest-effect risk genes. Overall, we find strong evidence that de novo mutations are associated with ASD apart from the risk for intellectual disability. Extending the transmission and de novo association test (TADA) to include small de novo deletions reveals 71 ASD risk loci, including 6 CNV regions (noted above) and 65 risk genes (FDR ≤ 0.1).

De Novo Insertions and Deletions of Predominantly Paternal Origin Are Associated with Autism Spectrum Disorder

Whole-exome sequencing (WES) studies have demonstrated the contribution of de novo loss-of-function single-nucleotide variants (SNVs) to autism spectrum disorder (ASD). However, challenges in the reliable detection of de novo insertions and deletions (indels) have limited inclusion of these variants in prior analyses. By applying a robust indel detection method to WES data from 787 ASD families (2,963 individuals), we demonstrate that de novo frameshift indels contribute to ASD risk (OR = 1.6; 95% CI = 1.0-2.7; p = 0.03), are more common in female probands (p = 0.02), are enriched among genes encoding FMRP targets (p = 6 × 10(-9)), and arise predominantly on the paternal chromosome (p < 0.001). On the basis of mutation rates in probands versus unaffected siblings, we conclude that de novo frameshift indels contribute to risk in approximately 3% of individuals with ASD. Finally, by observing clustering of mutations in unrelated probands, we uncover two ASD-associated genes: KMT2E (MLL5), a chromatin regulator, and RIMS1, a regulator of synaptic vesicle release.

Daily living skills in individuals with autism spectrum disorder from 2 to 21 years of age

Daily living skills (DLS), such as personal hygiene, meal preparation, and money management, are important to independent living. Research suggests that many individuals with autism spectrum disorder exhibit impairments in daily living skills relative to their cognitive skills. This study examined predictors of daily living skills attainment and trajectories of daily living skills in a longitudinal sample referred for possible autism spectrum disorder and followed from 2 to 21 years of age. Consistent with previous studies, participants with autism spectrum disorder and nonspectrum diagnoses showed continual development of daily living skills throughout childhood and adolescence. Early childhood nonverbal mental age was the strongest predictor of daily living skills attainment for both diagnostic groups. Group-based modeling suggested two distinct trajectories of daily living skills development for participants with autism spectrum disorder. Skill levels for both groups of young adults with autism spectrum disorder remained considerably below age level expectations. Whereas the “High-DLS” group gained approximately 12 years in daily living skills from T2 to T21, the “Low-DLS” group’s daily living skills improved 3–4 years over the 16- to 19-year study period. Nonverbal mental age, receptive language, and social-communication impairment at 2 years predicted High- versus Low-DLS group membership. Receiving greater than 20 h of parent-implemented intervention before age 3 was also associated with daily living skills trajectory. Results suggest that daily living skills should be a focus of treatment plans for individuals with autism spectrum disorder, particularly adolescents transitioning to young adulthood.

Multidimensional Influences on Autism Symptom Measures: Implications for Use in Etiological Research

OBJECTIVE Growing awareness that symptoms of autism spectrum disorder (ASD) transcend multiple diagnostic categories, and major advances in the identification of genetic syndromes associated with ASD, have led to widespread use of ASD symptom measures in etiologic studies of neurodevelopmental disorders. Insufficient consideration of potentially confounding factors such as cognitive ability or behavior problems can have important negative consequences in interpretation of findings, including erroneous estimation of associations between ASD and etiologic factors. METHOD Participants were 388 children 2 to 13 years old with diagnoses of ASD or another neurodevelopmental disorder without ASD. Receiver operating characteristics methods were used to assess the influence of IQ and emotional and behavioral problems on the discriminative ability of 3 widely used ASD symptom measures: the Social Responsiveness Scale (SRS), the Autism Diagnostic Interview-Revised (ADI-R), and the Autism Diagnostic Observation Schedule (ADOS). RESULTS IQ influenced the discriminative thresholds of the SRS and ADI-R, and emotional and behavioral problems affected the discriminative thresholds of the SRS, ADI-R, and ADOS. This resulted in low specificity of ASD cutoffs on the SRS and ADI-R for children with intellectual disability without ASD (27-42%) and low specificity across all 3 instruments for children without ASD with increased emotional and behavioral problems (36-59%). Adjustment for these characteristics resulted in improved discriminative ability for all of the ASD measures. CONCLUSION The findings indicate that scores on ASD symptom measures reflect far more than ASD symptoms. Valid interpretation of scores on these measures requires steps to account for the influences of IQ and emotional and behavioral problems.

Replication and Comparison of the Newly Proposed ADOS-2, Module 4 Algorithm in ASD Without ID: A Multi-site Study

Recent updates have been proposed to the Autism Diagnostic Observation Schedule-2 Module 4 diagnostic algorithm. This new algorithm, however, has not yet been validated in an independent sample without intellectual disability (ID). This multi-site study compared the original and revised algorithms in individuals with ASD without ID. The revised algorithm demonstrated increased sensitivity, but lower specificity in the overall sample. Estimates were highest for females, individuals with a verbal IQ below 85 or above 115, and ages 16 and older. Best practice diagnostic procedures should include the Module 4 in conjunction with other assessment tools. Balancing needs for sensitivity and specificity depending on the purpose of assessment (e.g., clinical vs. research) and demographic characteristics mentioned above will enhance its utility.

The autism symptom interview, school‐age: A brief telephone interview to identify autism spectrum disorders in 5‐to‐12‐year‐old children

This study reports on the initial validation of the Autism Symptom Interview (ASI), School‐Age, a brief (15–20 min) phone interview derived from questions from the Autism Diagnostic Interview‐Revised (ADI‐R). The ASI, School‐Age was administered by interviewers with minimal training to parents of children ages 5 to 12 who had all been previously identified with (or referred for assessment of) ASD or another neurodevelopmental disorder. Children then underwent a comprehensive assessment to determine a best‐estimate clinical diagnosis of ASD (n = 159) or non‐ASD (e.g. language disorder, intellectual disability, ADHD; n = 130). Clinicians who conducted the assessments were blind to ASI results. ROC analyses compared ASI scores to clinical diagnosis. Due to the small number of participants with non‐ASD diagnoses who were classified as nonverbal (i.e. not yet using phrases on a daily basis), it was not possible to assess sensitivity and specificity of the nonverbal algorithm in this sample. The verbal algorithm yielded a sensitivity of 0.87 (95% CI = 0.81–0.92) and a specificity of 0.62 (95% CI = 0.53–0.70). When used in conjunction with the Autism Diagnostic Observation Schedule (ADOS), sensitivity and specificity were 0.82 (95% CI = 0.74–0.88) and 0.92 (95% CI = 0.86–0.96), respectively. Internal consistency and test‐retest reliability were both excellent. Particularly for verbal school age children, the ASI may serve as a useful tool to more quickly ascertain or classify children with ASD for research or clinical triaging purposes. Additional data collection is underway to determine the utility of the ASI in children who are younger and/or nonverbal. Autism Res 2017, 10: 78–88.

Longitudinal follow‐up of academic achievement in children with autism from age 2 to 18

OBJECTIVE This study examined early predictors of and changes in school-age academic achievement and class placement in children referred for autism spectrum disorder (ASD) at age 2. METHOD Of 111 ASD referrals, 74 were diagnosed with ASD at age 18. Regression analyses were performed to identify age 3 predictors of achievement in arithmetic, passage comprehension, word reading, and spelling at ages 9 and 18. Linear Mixed Models were used to examine predictors of academic growth between ages 9 and 18. RESULTS Academic skills varied widely at 9 and 18, but were mostly commensurate with or higher than expected given cognitive levels. However, 22% (age 9) and 32% (age 18) of children with average/above average IQ showed below/low average achievement in at least one academic domain. Children who remained in general education/inclusion classrooms had higher achievement than those who moved to special education classrooms. Stronger cognitive skills at age 3 and 9 predicted better academic achievement and faster academic growth from age 9 to 18. Parent participation in intervention by age 3 predicted better achievement at age 9 and 18. CONCLUSIONS Many children with ASD achieve basic academic skills commensurate with or higher than their cognitive ability. However, more rigorous screening for learning difficulties may be important for those with average cognitive skills because a significant minority show relative academic delays. Interventions targeting cognitive skills and parent participation in early treatment may have cascading effects on long-term academic development.

Peabody Picture Vocabulary Test: Proxy for Verbal IQ in Genetic Studies of Autism Spectrum Disorder

This study assessed the utility of a brief assessment (the Peabody Picture Vocabulary Test—4th Edition; PPVT4) as a proxy for verbal IQ (VIQ) in large-scale studies of autism spectrum disorder (ASD). In a sample of 2,420 proband with ASD, PPVT4:IQ correlations were strong. PPVT4 scores were, on average, 5.46 points higher than VIQ; 79% of children had PPVT4 scores within one standard deviation (+/−15) of their VIQ and 90% were similarly classified as having abilities above or below 70 on both measures. Distributions of PPVT4 and VIQ by de novo mutation status were highly similar. These results strongly support the utility of PPVT4 as a proxy for VIQ in large-scale ASD studies, particularly for genetic investigations.

Children with autism spectrum disorder who improve with fever: Insights from the Simons Simplex Collection

Literature indicates that some children with ASD may show behavioral improvements during fever; however, little is known about the behavioral profiles of these children. This study aims to (a) investigate the subset of children who show parent‐reported behavioral improvements associated with fever and (b) compare the demographic, behavioral, and genetic characteristics of this subset of children to children whose parents report no change during fever. Parents of 2,152 children from the Simons Simplex Collection provided information about whether and in which areas their child improved during fever. Children were randomly assigned into discovery or replication samples. In discovery analyses, children who reportedly improved with fever (Improve Group) were compared to those who reportedly did not improve (No Improve Group) on demographics, medical history, ASD symptoms, adaptive skills, and presence of de novo ASD‐associated mutations. Significant and marginal results from discovery analyses were tested in the replication sample. Parent reports of 17% of children indicated improvements during fever across a range of domains. Discovery and replication analyses revealed that the Improve Group had significantly lower non‐verbal cognitive skills (NVIQ) and language levels and more repetitive behaviors. Groups did not differ on demographic variables, parent‐report of current ASD symptoms or the presence of de novo mutations. Understanding the profiles of children who improve during episodes of fever may provide insights into innovative treatments for ASD. Autism Res 2018, 11: 175–184.