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To characterize the clinical phenotype of the recurrent copy-number variation (CNV) at 1q21.1, we assessed the psychiatric and medical phenotypes of 1q21.1 deletion and duplication carriers ascertained through clinical genetic testing and family member cascade testing, with particular emphasis on dimensional assessment across multiple functional domains. Nineteen individuals with 1q21.1 deletion, 19 individuals with the duplication, and 23 familial controls (noncarrier siblings and parents) spanning early childhood through adulthood were evaluated for psychiatric, neurologic, and other medical diagnoses, and their cognitive, adaptive, language, motor, and neurologic domains were also assessed. Twenty-eight individuals with 1q21.1 CNVs (15 deletion, 13 duplication) underwent structural magnetic resonance brain imaging. Probands with 1q21.1 CNVs presented with a range of psychiatric, neurologic, and medical disorders. Deletion and duplication carriers shared several features, including borderline cognitive functioning, impaired fine and gross motor functioning, articulation abnormalities, and hypotonia. Increased frequency of Autism Spectrum Disorder (ASD) diagnosis, increased ASD symptom severity, and increased prevalence of macrocephaly were observed in the duplication relative to deletion carriers, whereas reciprocally increased prevalence of microcephaly was observed in the deletion carriers. Individuals with 1q21.1 deletions or duplications exhibit consistent deficits on motor and cognitive functioning and abnormalities in head circumference.

Limited research exists regarding the role of teachers in screening for Autism Spectrum Disorders (ASD). The current study examined the use of the Social Communication Questionnaire (SCQ) and Social Responsiveness Scale (SRS) as completed by parents and teachers about school-age children from the Simons Simplex Collection. Using the recommended cutoff scores in the manuals and extant literature, the teacher-completed SCQ and SRS yielded lower sensitivity and specificity values than would be desirable; however, lowering the cutoff scores on both instruments improved sensitivity and specificity to more adequate levels for screening purposes. Using the adjusted cutoff scores, the SRS teacher form appears to be a slightly better screener than the SCQ. Implications and limitations are discussed, as well as areas for future research.

We recently reported a deletion of exon 2 of the trimethyllysine hydroxylase epsilon (TMLHE) gene in a proband with autism. TMLHE maps to the X chromosome and encodes the first enzyme in carnitine biosynthesis, 6-N-trimethyllysine dioxygenase. Deletion of exon 2 of TMLHE causes enzyme deficiency, resulting in increased substrate concentration (6-N-trimethyllysine) and decreased product levels (3-hydroxy-6-N-trimethyllysine and γ-butyrobetaine) in plasma and urine. TMLHE deficiency is common in control males (24 in 8,787 or 1 in 366) and was not significantly increased in frequency in probands from simplex autism families (9 in 2,904 or 1 in 323). However, it was 2.82-fold more frequent in probands from male-male multiplex autism families compared with controls (7 in 909 or 1 in 130; P = 0.023). Additionally, six of seven autistic male siblings of probands in male-male multiplex families had the deletion, suggesting that TMLHE deficiency is a risk factor for autism (metaanalysis Z-score = 2.90 and P = 0.0037), although with low penetrance (2–4%). These data suggest that dysregulation of carnitine metabolism may be important in nondysmorphic autism; that abnormalities of carnitine intake, loss, transport, or synthesis may be important in a larger fraction of nondysmorphic autism cases; and that the carnitine pathway may provide a novel target for therapy or prevention of autism.

The present study sought to explore the motor phenotype of 16p11.2 deletion and duplication syndromes in a sample of probands (50.5% female), ranging in age from 6 months to 17 years. The extent and variability of motor dysfunction was assessed among carriers of 16p11.2 deletion and duplication syndromes, non-carrier siblings, and non-familial controls using several standardized performance- and informant-based measures. Analyses indicated that probands with either 16p11.2 deletion or duplication syndrome exhibited poorer motor performance compared to familial and non-familial controls. While deletion and duplication carriers performed similarly across several measures of fine-motor functioning, deletion carriers scored significantly lower than duplication carriers on the MABC-2, a comprehensive assessment of both gross- and fine-motor skills. Males and females with a 16p11.2 CNV performed worse on motor tasks compared to non-carrier controls, but there were no sex differences within carrier groups. Results underscore motor impairment as a clear feature of 16p11.2 deletion and duplication syndromes in infancy through adolescence. Motor functioning is discussed as a facet with strong evidence to support early identification practices of ASD.

Chromosome 15q13.3 represents a hotspot for genomic rearrangements due to repetitive sequences mediating nonallelic homologous recombination. Deletions of 15q13.3 have been identified in the context of multiple neurological and psychiatric disorders, but a prospective clinical and behavioral assessment of affected individuals has not yet been reported. Eighteen subjects with 15q13.3 microdeletion underwent a series of behavioral assessments, along with clinical history and physical examination, to comprehensively define their behavioral phenotypes. Cognitive deficits are the most prevalent feature in 15q13.3 deletion syndrome, with an average nonverbal IQ of 60 among the patients studied. Autism spectrum disorder was highly penetrant, with 31% of patients meeting clinical criteria and exceeding cutoff scores on both ADOS-2 and ADI-R. Affected individuals exhibited a complex pattern of behavioral abnormalities, most notably hyperactivity, attention problems, withdrawal, and externalizing symptoms, as well as impairments in functional communication, leadership, adaptive skills, and activities of daily living. The 15q13.3 deletion syndrome encompasses a heterogeneous behavioral phenotype that poses a major challenge to parents, caregivers, and treating providers. Further work to more clearly delineate genotype–phenotype relationships in 15q13.3 deletions will be important for anticipatory guidance and development of targeted therapies. Genet Med18 11, 1111–1118.

SPARK launched in 2016 to build a US cohort of autistic individuals and their family members. Enrollment includes online consent to share data and optional consent to provide saliva for genomic analysis. SPARK's recruitment strategies include social media and support of a nation-wide network of clinical sites. This study evaluates SPARK's recruitment strategies to enroll a core study population. Individuals who joined between January 31, 2018, and May 29, 2019 were included in the analysis. Data include sociodemographic characteristics, clinical site referral, the website URL used to join, how the participant heard about SPARK, enrollment completion (online registration, study consents, and returning saliva sample), and completion of the baseline questionnaire. Logistic regressions were performed to evaluate the odds of core participant status (completing enrollment and baseline questionnaire) by recruitment strategy. In total, 31,715 individuals joined during the study period, including 40% through a clinical site. Overall, 88% completed online registration, 46% returned saliva, and 38% were core participants. Those referred by a clinical site were almost twice as likely to be core participants. Those who directly visited the SPARK website or performed a Google search were more likely to be core participants than those who joined through social media. Being a core participant may be associated with the \"personal\" connection and support provided by a clinical site and/or site staff, as well as greater motivation to seek research opportunities. Findings from this study underscore the value of adopting a multimodal recruitment approach that combines social media and a physical presence.

Under enrollment of participants in clinical research is costly and delays study completion to impact public health. Given that research personnel make decisions about which strategies to pursue and participants are the recipients of these efforts, we surveyed research staff ( = 52) and participants ( = 4,144) affiliated with SPARK (Simons Foundation Powering Autism for Knowledge) - the largest study of autism in the U.S. - to understand their perceptions of effective recruitment strategies. In Study 1, research personnel were asked to report recruitment strategies that they tried for SPARK and to indicate which ones they would and would not repeat/recommend. In Study 2, SPARK participants were asked to indicate all the ways they heard about the study prior to enrollment and which one was most influential in their decisions to enroll. Staff rated Participants most often heard about SPARK via Results suggest that a combination of strategies is likely to be most effective in reaching diverse audiences. Findings have implications for the selection of strategies that meet a study's specific needs, as well as recruitment-strategy \"combinations\" that may enhance the influence of outreach efforts.

The broad autism phenotype (BAP) refers to the phenotypic expression of an underlying genetic liability to autism, manifest in non-autistic relatives. This study examined the relationship among the Broad Autism Phenotype Questionnaire (BAPQ), Social Responsiveness Scale: Adult Research Version (SRS:ARV), and Family History Interview (FHI) in a large, multi-site study of 1,650 simplex families (Simons Simplex Collection). Correlations between the BAPQ and SRS:ARV Total scores were moderate, and correlations between FHI ratings and SRS:ARV and BAPQ were significant but weak. Overall, the results suggested that BAP traits occur at low rates in simplex families, and rates vary significantly depending upon the measure utilized. Implications include the need for multiple informants, and the assessment of distinct BAP traits in large-scale genetic studies of individuals with ASD.

Approximately one-third of children with autism spectrum disorder (ASD) reportedly lose skills within the first 3 years, yet a causal mechanism remains elusive. Considering evidence of strong genetic effects for ASD and findings that distinct phenotypes in ASD associate with specific genetic events, we examined rates of parent-reported regression in the Simons Simplex Collection with likely gene disrupting mutations from five distinct classes: FMRP target genes, genes encoding chromatin modifiers, genes expressed preferentially in embryos, genes encoding postsynaptic density proteins, and essential genes. Children with ASD and mutations in postsynaptic density genes were more likely to experience regression, while a trend suggested that children with ASD and mutations in embryonic genes were less likely to have skill losses.

Perceptual processing in autism spectrum disorder (ASD) is marked by superior low-level task performance and inferior complex-task performance. This observation has led to theories of defective integration in ASD of local parts into a global percept. Despite mixed experimental results, this notion maintains widespread influence and has also motivated recent theories of defective multisensory integration in ASD. Impaired ASD performance in tasks involving classic random dot visual motion stimuli, corrupted by noise as a means to manipulate task difficulty, is frequently interpreted to support this notion of global integration deficits. By manipulating task difficulty independently of visual stimulus noise, here we test the hypothesis that heightened sensitivity to noise, rather than integration deficits, may characterize ASD. We found that although perception of visual motion through a cloud of dots was unimpaired without noise, the addition of stimulus noise significantly affected adolescents with ASD, more than controls. Strikingly, individuals with ASD demonstrated intact multisensory (visual–vestibular) integration, even in the presence of noise. Additionally, when vestibular motion was paired with pure visual noise, individuals with ASD demonstrated a different strategy than controls, marked by reduced flexibility. This result could be simulated by using attenuated (less reliable) and inflexible (not experience-dependent) Bayesian priors in ASD. These findings question widespread theories of impaired global and multisensory integration in ASD. Rather, they implicate increased sensitivity to sensory noise and less use of prior knowledge in ASD, suggesting increased reliance on incoming sensory information. Significance Descriptions of impaired coherent motion perception in autism spectrum disorder (ASD) underlie theories that individuals with ASD have difficulty integrating local “parts” into a global percept. This notion maintains widespread influence and motivates recent theories of defective multisensory integration in ASD. However, heightened sensitivity to sensory noise, used to manipulate task difficulty in predominant visual motion stimuli, may provide an alternative explanation for impaired performance. Here we indeed found increased sensitivity in ASD to sensory noise. Noiseless motion perception and multisensory integration (even with noise) were unimpaired. These findings question prevalent theories of global and multisensory integration deficits in ASD. Rather, they suggest increased reliance on—and sensitivity to—incoming sensory information and less use of prior knowledge in ASD.