Neurodevelopmental functioning in probands and non-proband carriers of 22q11.2 microduplication.

Microduplication of the LCR22-A to LCR22-D region on chromosome 22q11.2 is a recurrent copy number variant found in clinical populations undergoing chromosomal microarray, and at lower frequency in controls. Often inherited, there is limited data on intellectual (IQ) and psychological functioning, particularly in those individuals ascertained through a family member rather than because of neurodevelopmental disorders. To investigate the range of cognitive-behavioral phenotypes associated with 22q11.2 duplication, we studied both probands and their non-proband carrier relatives. Twenty-two individuals with 22q11.2 duplication (10 probands, 12 non-proband carriers) were prospectively assessed with a battery of neuropsychological tests, physical examination, and medical record review. Assessment measures with standardized norms included IQ, academic, adaptive, psychiatric, behavioral, and social functioning. IQ and academic skills were within the average range, with a trend toward lower scores in probands versus non-probands. Adaptive skills were within age expectations. Prevalence of attention deficits (probands only) and anxiety (both groups) was high compared with norms. The prevalence of autism spectrum disorder was relatively low (5% of total sample). Assessment of both probands and non-probands with 22q11.2 duplication suggests that the phenotypic spectrum with respect to neurodevelopment overlaps significantly with the general population. IQ and academic abilities are in the average range for most of the individuals with 22q11.2 duplication in our study, regardless of ascertainment as a proband or non-proband relative. Symptoms of attention deficit and anxiety were identified, which require further study. Results of this study further clarify the phenotype of individuals with 22q11.2 duplication, and provides important information for genetic counseling regarding this recurrent copy number variant.

"Going Mobile"-increasing the reach of parent-mediated intervention for toddlers with ASD via group-based and virtual delivery.

Evidence supports early intervention for toddlers with ASD, but barriers to access remain, including system costs, workforce constraints, and a range of family socio-demographic factors. An urgent need exists for innovative models that maximize resource efficiency and promote widespread timely access. We examined uptake and outcomes from 82 families participating in a parent-mediated intervention comprising group-based learning and individual coaching, delivered either in-person (n = 45) or virtually (n = 37). Parents from diverse linguistic, ethnic, and educational backgrounds gained intervention skills and toddlers evidenced significant social-communication gains. Few differences emerged across socio-demographic factors or delivery conditions. Findings highlight the feasibility, acceptability, and promise of group-based learning when combined with individual coaching, with added potential to increase program reach via virtual delivery.

Atypical autism in a boy with double duplication of 22q11.2: implications of increasing dosage.

Duplication of chromosome 22q11.2 (LCR A-D) has been reported at higher frequencies in clinical samples than the general population, but phenotypes vary widely. Triplication (4 copies) is rare, but studying the associated phenotype may provide insight into dosage-sensitivity of the genes in this chromosomal interval. We describe a proband with a triplication, specifically a "double duplication" (two copies per chromosome) of the 22q11.2 region, while his parents and two siblings each have a single duplication (3 copies). The proband had a heart malformation, dysmorphic features, and learning and socialization deficits, whereas the other family members did not. This family illustrates that while duplication of the 22q11.2 may not be sufficient to cause clinically significant neurodevelopmental or health-related phenotypes, triplication of the same region may result in a phenotype characterized by a mild neurodevelopmental disorder, facial dysmorphism, and possibly cardiac anomalies.

Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder.

We are performing whole-genome sequencing of families with autism spectrum disorder (ASD) to build a resource (MSSNG) for subcategorizing the phenotypes and underlying genetic factors involved. Here we report sequencing of 5,205 samples from families with ASD, accompanied by clinical information, creating a database accessible on a cloud platform and through a controlled-access internet portal. We found an average of 73.8 de novo single nucleotide variants and 12.6 de novo insertions and deletions or copy number variations per ASD subject. We identified 18 new candidate ASD-risk genes and found that participants bearing mutations in susceptibility genes had significantly lower adaptive ability (P = 6 × 10-4). In 294 of 2,620 (11.2%) of ASD cases, a molecular basis could be determined and 7.2% of these carried copy number variations and/or chromosomal abnormalities, emphasizing the importance of detecting all forms of genetic variation as diagnostic and therapeutic targets in ASD.

Can parents' concerns predict autism spectrum disorder? A prospective study of high-risk siblings from 6 to 36 months of age.

OBJECTIVE: This prospective study characterized parents' concerns about infants at high risk for developing autism spectrum disorder (ASD; each with an older sibling with ASD) at multiple time points in the first 2 years, and assessed their relation to diagnostic outcome at 3 years. METHOD: Parents of low-risk controls (LR) and high-risk infant siblings (HR) reported any concerns that they had regarding their children's development between 6 and 24 months of age regarding sleep, diet, sensory behavior, gross/fine motor skills, repetitive movements, communication, communication regression, social skills, play, and behavioral problems, using a parent concern form designed for this study. At 3 years of age, an independent, gold-standard diagnostic assessment for ASD was conducted for all participants. RESULTS: As predicted, parents of HR children who received an ASD diagnosis reported more concerns than parents of LR and HR children who did not have ASD. The total number of concerns predicted a subsequent diagnosis of ASD as early as 12 months within the HR group. Concerns regarding sensory behavior and motor development predicted a subsequent diagnosis of ASD as early as 6 months, whereas concerns about social communication and repetitive behaviors did not predict diagnosis of ASD until after 12 months. CONCLUSION: Parent-reported concerns can improve earlier recognition of ASD in HR children.