Integrating de novo and inherited variants in 42,607 autism cases identifies mutations in new moderate-risk genes.

To capture the full spectrum of genetic risk for autism, we performed a two-stage analysis of rare de novo and inherited coding variants in 42,607 autism cases, including 35,130 new cases recruited online by SPARK. We identified 60 genes with exome-wide significance (P < 2.5 × 10-6), including five new risk genes (NAV3, ITSN1, MARK2, SCAF1 and HNRNPUL2). The association of NAV3 with autism risk is primarily driven by rare inherited loss-of-function (LoF) variants, with an estimated relative risk of 4, consistent with moderate effect. Autistic individuals with LoF variants in the four moderate-risk genes (NAV3, ITSN1, SCAF1 and HNRNPUL2; n = 95) have less cognitive impairment than 129 autistic individuals with LoF variants in highly penetrant genes (CHD8, SCN2A, ADNP, FOXP1 and SHANK3) (59% vs 88%, P = 1.9 × 10-6). Power calculations suggest that much larger numbers of autism cases are needed to identify additional moderate-risk genes.

Consistency of parent-report SLC6A1 data in Simons Searchlight with Provider-Based Publications.

BACKGROUND: SLC6A1-related disorder is a recently identified, rare, genetic neurodevelopmental disorder that is associated with loss-of-function variants in SLC6A1. This gene encodes GABA transporter type I that is responsible for re-uptake of GABA from the synapse into the pre-synaptic terminal or circulating neuroglia. Based upon retrospective review of published cases and available research databases including Epi25 collective and SLC6A1 Connect patient database, the phenotypic spectrum is broad and includes developmental delay, epilepsy, and autism or autistic traits. SLC6A1 is one of the genes included in the Simons Searchlight registry, which includes standardized data collection across genetically identified neurodevelopmental conditions. METHODS: In this study, we compare parent-report measures of phenotypic features in the Simons Searchlight registry to previously published, provider-reported cases to assess if parent-report measures are consistent with what has been reported in the literature. RESULTS: There were 116 participants in the provider-reported dataset compared to 43 individuals in the caregiver-reported dataset. Carriers in Searchlight had 83 unique pathogenic or likely pathogenic variants in SLC6A1, which were predominantly missense or nonsense variants. There was no significant difference between groups for the prevalence of developmental delay, ASD, or ADHD. Caregivers more often reported hypotonia, while epilepsy was slightly more frequently reported by providers. CONCLUSIONS: We propose that standardized parent-report data collection methods are consistent with provider reports on many core features of SLC6A1-related disorder. The availability of patient registries and standardized natural history studies may fill an important need in clinical trial readiness programs, with larger sample sizes than smaller published case series.

Availability of Services and Caregiver Burden: Supporting Individuals With Neurogenetic Conditions During the COVID-19 Pandemic.

Because of the COVID-19 pandemic, in-person services for individuals with neurodevelopmental disabilities were disrupted globally, resulting in a transition to remote delivery of services and therapies. For individuals with neurogenetic conditions, reliance on nonclinical caregivers to facilitate all therapies and care was unprecedented. The study aimed to (1) describe caregivers' reported impact on their dependent's services, therapies, medical needs, and impact on themselves as a result of the COVID-19 pandemic and (2) assess the relationship between the extent of disruption of services and the degree of self-reported caregiver burden. Two online questionnaires were completed by caregivers participating in Simons Searchlight in April and May 2020. Surveys were completed by caregivers of children or dependent adults with neurodevelopmental genetic conditions in Simons Searchlight. Caregivers reported that the impact of the COVID-19 pandemic moderately or severely disrupted services, therapies, or medical supports. The majority of caregivers were responsible for providing some aspect of therapy. Caregivers reported "feeling stressed but able to deal with problems as they arise," and reported lower anxiety at follow-up. Caregivers reported that telehealth services were not meeting the needs of those with complex medical needs. Future surveys will assess if and how medical systems, educational programs, therapists, and caregivers adapt to the challenges arising during the COVID-19 pandemic.

16p11.2 deletion syndrome.

The 16p11.2 BP4 and BP5 region, is a recurrent ∼600kb copy number variant (CNV), and deletions are one of the most frequent etiologies of neurodevelopmental disorders and autism spectrum disorder with an incidence of approximately 1/2000. Deletion carriers have delays in early neurodevelopment that most specifically impair speech, phonology and language in 70%. Intelligence quotient is shifted 1.8 standard deviations lower than family controls without the deletion. Other common neurobehavioral conditions include motor coordination difficulties (60%) and autism (20-25%). Unprovoked seizures are common (24%) and readily treated and resolve with age in many. Obesity evolves throughout childhood and by adulthood 75% are obese. Congenital anomalies are more common than the general population. The deletion is associated with an increase in brain volumes across all areas of the brain, changes in the white matter microstructural properties, and early electrophysiological cortical responses from auditory cortex. Studies of genetically defined conditions, particularly CNVs that are not associated with profound disabilities, provide homogeneity to study genetic impact on brain development, structure, and function to better understand complex neurobehavioral phenotypes such as autism.

Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes.

Autism spectrum disorder (ASD) is a genetically heterogeneous condition, caused by a combination of rare de novo and inherited variants as well as common variants in at least several hundred genes. However, significantly larger sample sizes are needed to identify the complete set of genetic risk factors. We conducted a pilot study for SPARK (SPARKForAutism.org) of 457 families with ASD, all consented online. Whole exome sequencing (WES) and genotyping data were generated for each family using DNA from saliva. We identified variants in genes and loci that are clinically recognized causes or significant contributors to ASD in 10.4% of families without previous genetic findings. In addition, we identified variants that are possibly associated with ASD in an additional 3.4% of families. A meta-analysis using the TADA framework at a false discovery rate (FDR) of 0.1 provides statistical support for 26 ASD risk genes. While most of these genes are already known ASD risk genes, BRSK2 has the strongest statistical support and reaches genome-wide significance as a risk gene for ASD (p-value = 2.3e-06). Future studies leveraging the thousands of individuals with ASD who have enrolled in SPARK are likely to further clarify the genetic risk factors associated with ASD as well as allow accelerate ASD research that incorporates genetic etiology.

Developmental trajectories for young children with 16p11.2 copy number variation.

Copy number variation at 16p11.2 is associated with diverse phenotypes but little is known about the early developmental trajectories and emergence of the phenotype. This longitudinal study followed 56 children with the 16p11.2 BP4-BP5 deletion or duplication between the ages of 6 months and 8 years with diagnostic characterization and dimensional assessment across cognitive, adaptive, and behavioral domains. Linear mixed modeling revealed distinct developmental trajectories with deletions showing VIQ gains but declines in motor and social abilities while duplications showed VIQ gains and steady development across other domains. Nonparametric analyses suggest distinct trajectories and early cognitive abilities for deletion carriers who are ultimately diagnosed with intellectual disability and developmental coordination disorder as well as distinct trajectories and early social communication and cognitive abilities for duplication carriers diagnosed with ASD and intellectual disability. Findings provide predictions for patient developmental trajectories, insight into mean functioning of individuals with 16p11.2 at early ages, and highlight the need for ongoing monitoring of social and motor functioning and behavioral symptomatology to improve treatment planning. © 2017 Wiley Periodicals, Inc.

Defining the Effect of the 16p11.2 Duplication on Cognition, Behavior, and Medical Comorbidities.

IMPORTANCE: The 16p11.2 BP4-BP5 duplication is the copy number variant most frequently associated with autism spectrum disorder (ASD), schizophrenia, and comorbidities such as decreased body mass index (BMI). OBJECTIVES: To characterize the effects of the 16p11.2 duplication on cognitive, behavioral, medical, and anthropometric traits and to understand the specificity of these effects by systematically comparing results in duplication carriers and reciprocal deletion carriers, who are also at risk for ASD. DESIGN, SETTING, AND PARTICIPANTS: This international cohort study of 1006 study participants compared 270 duplication carriers with their 102 intrafamilial control individuals, 390 reciprocal deletion carriers, and 244 deletion controls from European and North American cohorts. Data were collected from August 1, 2010, to May 31, 2015 and analyzed from January 1 to August 14, 2015. Linear mixed models were used to estimate the effect of the duplication and deletion on clinical traits by comparison with noncarrier relatives. MAIN OUTCOMES AND MEASURES: Findings on the Full-Scale IQ (FSIQ), Nonverbal IQ, and Verbal IQ; the presence of ASD or other DSM-IV diagnoses; BMI; head circumference; and medical data. RESULTS: Among the 1006 study participants, the duplication was associated with a mean FSIQ score that was lower by 26.3 points between proband carriers and noncarrier relatives and a lower mean FSIQ score (16.2-11.4 points) in nonproband carriers. The mean overall effect of the deletion was similar (-22.1 points; P < .001). However, broad variation in FSIQ was found, with a 19.4- and 2.0-fold increase in the proportion of FSIQ scores that were very low (≤40) and higher than the mean (>100) compared with the deletion group (P < .001). Parental FSIQ predicted part of this variation (approximately 36.0% in hereditary probands). Although the frequency of ASD was similar in deletion and duplication proband carriers (16.0% and 20.0%, respectively), the FSIQ was significantly lower (by 26.3 points) in the duplication probands with ASD. There also were lower head circumference and BMI measurements among duplication carriers, which is consistent with the findings of previous studies. CONCLUSIONS AND RELEVANCE: The mean effect of the duplication on cognition is similar to that of the reciprocal deletion, but the variance in the duplication is significantly higher, with severe and mild subgroups not observed with the deletion. These results suggest that additional genetic and familial factors contribute to this variability. Additional studies will be necessary to characterize the predictors of cognitive deficits.

Clinical phenotype of the recurrent 1q21.1 copy-number variant.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Individuals with 1q21.1 deletions or duplications exhibit consistent deficits on motor and cognitive functioning and abnormalities in head circumference.Genet Med 18 4, 341-349.

The cognitive and behavioral phenotype of the 16p11.2 deletion in a clinically ascertained population.

BACKGROUND: Deletion of the recurrent ~600 kb BP4-BP5 chromosomal region 16p11.2 has been associated with a wide range of neurodevelopmental outcomes. METHODS: To clarify the phenotype of 16p11.2 deletion, we examined the psychiatric and developmental presentation of predominantly clinically referred individuals, with a particular emphasis on broader autism phenotype characteristics in individuals with recurrent ~600 kb chromosome 16p11.2 deletions. Using an extensive standardized assessment battery across three clinical sites, 85 individuals with the 16p11.2 deletion and 153 familial control subjects were evaluated for symptom presentation and clinical diagnosis. RESULTS: Individuals with the 16p11.2 deletion presented with a high frequency of psychiatric and developmental disorders (>90%). The most commonly diagnosed conditions were developmental coordination disorder, phonologic processing disorder, expressive and receptive language disorders (71% of individuals >3 years old with a speech and language-related disorder), and autism spectrum disorder. Individuals with the 16p11.2 deletion not meeting diagnostic criteria for autism spectrum disorder had a significantly higher prevalence of autism-related characteristics compared with the familial noncarrier control group. Individuals with the 16p11.2 deletion had a range of intellectual ability, but IQ scores were 26 points lower than noncarrier family members on average. CONCLUSIONS: Clinically referred individuals with the 16p11.2 deletion have high rates of psychiatric and developmental disorders and provide a genetically well-defined group to study the emergence of developmental difficulties, particularly associated with the broader autism phenotype.