Peter Szatmari

Structural Variation of Chromosomes in Autism Spectrum Disorder

Structural variation (copy number variation [CNV] including deletion and duplication, translocation, inversion) of chromosomes has been identified in some individuals with autism spectrum disorder (ASD), but the full etiologic role is unknown. We performed genome-wide assessment for structural abnormalities in 427 unrelated ASD cases via single-nucleotide polymorphism microarrays and karyotyping. With microarrays, we discovered 277 unbalanced CNVs in 44% of ASD families not present in 500 controls (and re-examined in another 1152 controls). Karyotyping detected additional balanced changes. Although most variants were inherited, we found a total of 27 cases with de novo alterations, and in three (11%) of these individuals, two or more new variants were observed. De novo CNVs were found in approximately 7% and approximately 2% of idiopathic families having one child, or two or more ASD siblings, respectively. We also detected 13 loci with recurrent/overlapping CNV in unrelated cases, and at these sites, deletions and duplications affecting the same gene(s) in different individuals and sometimes in asymptomatic carriers were also found. Notwithstanding complexities, our results further implicate the SHANK3-NLGN4-NRXN1 postsynaptic density genes and also identify novel loci at DPP6-DPP10-PCDH9 (synapse complex), ANKRD11, DPYD, PTCHD1, 15q24, among others, for a role in ASD susceptibility. Our most compelling result discovered CNV at 16p11.2 (p = 0.002) (with characteristics of a genomic disorder) at approximately 1% frequency. Some of the ASD regions were also common to mental retardation loci. Structural variants were found in sufficiently high frequency influencing ASD to suggest that cytogenetic and microarray analyses be considered in routine clinical workup.

Behavioral manifestations of autism in the first year of life

In the interest of more systematically documenting the early signs of autism, and of testing specific hypotheses regarding their underlying neurodevelopmental substrates, we have initiated a longitudinal study of high‐risk infants, all of whom have an older sibling diagnosed with an autistic spectrum disorder. Our sample currently includes 150 infant siblings, including 65 who have been followed to age 24 months, who are the focus of this paper. We have also followed a comparison group of low‐risk infants. Our measures include a novel observational scale (the first, to our knowledge, that is designed to assess autism‐specific behavior in infants), a computerized visual orienting task, and standardized measures of temperament, cognitive and language development. Our preliminary results indicate that by 12 months of age, siblings who are later diagnosed with autism may be distinguished from other siblings and low‐risk controls on the basis of: (1) several specific behavioral markers, including atypicalities in eye contact, visual tracking, disengagement of visual attention, orienting to name, imitation, social smiling, reactivity, social interest and affect, and sensory‐oriented behaviors; (2) prolonged latency to disengage visual attention; (3) a characteristic pattern of early temperament, with marked passivity and decreased activity level at 6 months, followed by extreme distress reactions, a tendency to fixate on particular objects in the environment, and decreased expression of positive affect by 12 months; and (4) delayed expressive and receptive language. We discuss these findings in the context of various neural networks thought to underlie neurodevelopmental abnormalities in autism, including poor visual orienting. Over time, as we are able to prospectively study larger numbers and to examine interrelationships among both early‐developing behaviors and biological indices of interest, we hope this work will advance current understanding of the neurodevelopmental origins of autism.

The Prevalence of Anxiety and Mood Problems among Children with Autism and Asperger Syndrome

The objective of this study was to report on the prevalence and correlates of anxiety and mood problems among 9- to 14- year-old children with Asperger syndrome (AS) and high-functioning autism. Children who received a diagnosis of autism (n 40) or AS (n 19) on a diagnostic interview when they were 4 to 6 years of age were administered a battery of cognitive and behavioural measures. Families were contacted roughly 6 years later (at mean age of 12 years) and assessed for evidence of psychiatric problems including mood and anxiety disorders. Compared with a sample of 1751 community children, AS and autistic children demonstrated a greater rate of anxiety and depression problems. These problems had a significant impact on their overall adaptation. There were, however, no differences in the number of anxiety and mood problems between the AS and autistic children within this high-functioning cohort. The number of psychiatric problems was not correlated with early autistic symptoms but was predicted to a small extent by early verbal/non-verbal IQ discrepancy scores. These data indicate that high-functioning PDD children are at greater risk for mood and anxiety problems than the general population but the correlates and risk factors for these comorbid problems remain unclear.

Contribution of SHANK3 Mutations to Autism Spectrum Disorder

Mutations in SHANK3, which encodes a synaptic scaffolding protein, have been described in subjects with an autism spectrum disorder (ASD). To assess the quantitative contribution of SHANK3 to the pathogenesis of autism, we determined the frequency of DNA sequence and copy-number variants in this gene in 400 ASD-affected subjects ascertained in Canada. One de novo mutation and two gene deletions were discovered, indicating a contribution of 0.75% in this cohort. One additional SHANK3 deletion was characterized in two ASD-affected siblings from another collection, which brings the total number of published mutations in unrelated ASD-affected families to seven. The combined data provide support that haploinsufficiency of SHANK3 can cause a monogenic form of autism in sufficient frequency to warrant consideration in clinical diagnostic testing.

Mutations in the SHANK2 synaptic scaffolding gene in autism spectrum disorder and mental retardation

Using microarrays, we identified de novo copy number variations in the SHANK2 synaptic scaffolding gene in two unrelated individuals with autism-spectrum disorder (ASD) and mental retardation. DNA sequencing of SHANK2 in 396 individuals with ASD, 184 individuals with mental retardation and 659 unaffected individuals (controls) revealed additional variants that were specific to ASD and mental retardation cases, including a de novo nonsense mutation and seven rare inherited changes. Our findings further link common genes between ASD and intellectual disability.

Asperger's syndrome and autism: neurocognitive aspects

The objectives of this study were to see: (1) whether children with Aspergers Syndrome (AS) have similar neurocognitive deficits compared to nonretarded, or high-functioning autistic (HFA) children; and (2) whether the essential cognitive deficit among these children is in language or abstract problem solving. Subjects with AS, HFA, and a control group of socially impaired child psychiatric outpatient controls (OPC) were compared on a battery of neuropsychological tests. The results indicated that the AS and HFA groups differed little but that large differences from the OPC were observed on all tests. When the AS and HFA with FSIQ above 85 were compared to the OPC, outstanding deficits on motor coordination, language comprehension, and facial recognition were observed. Finally, some evidence is presented to suggest that the pattern of deficits of AS and HFA subjects varied by developmental level. The implications of these results for a neurological theory of autism are discussed.

Integrating Assessment Data from Multiple Informants

OBJECTIVE To examine the consequences for measurement of child psychiatric disorder (conduct and oppositional disorders) of not integrating the data on the same individual from different informants compared with integrating the information from parents and teachers, using three different strategies. METHOD Data for the study came from problem checklist assessments done by parents and teachers of children aged 6 to 16 years (N = 1,134) selected with known probability from a general population sample and from structured interviews obtained in a stratified random subsample (n = 251). RESULTS As expected, parent-teacher agreement was low. The pattern of associated features of disorder was found to vary markedly in parent-identified compared with teacher-identified disorder. Furthermore, combining informants had the disadvantage of masking the distinctive patterns of associated features noted in informant-specific disorders. Finally, by treating disorder as informant-specific, the internal properties of the measure are not generally inferior to those obtained by combining informants in various ways. CONCLUSION Child psychiatric disorders should be conceptualized as informant-specific phenomena.

Sex Differences in Pervasive Developmental Disorders.

Assessed differences in sex ratio, severity of associated mental retardation, and various metrics of severity of autism in autistic, PDD-NOS, and developmentally disordered (non-PDD) cases. Males with autism were more frequent than females, particular at higher IQ levels. The three clinical groups differed, in expected ways, in the various measures of severity of autism with the PDD-NOS cases being intermediate between the strictly diagnosed autistic group and the non-PDD developmental disordered group. Sex differences were primarily confined to IQ; sex differences in other metrics of severity of autism were not prominent. Implications for future research are discussed.

Detection of Clinically Relevant Genetic Variants in Autism Spectrum Disorder by Whole-Genome Sequencing

Autism Spectrum Disorder (ASD) demonstrates high heritability and familial clustering, yet the genetic causes remain only partially understood as a result of extensive clinical and genomic heterogeneity. Whole-genome sequencing (WGS) shows promise as a tool for identifying ASD risk genes as well as unreported mutations in known loci, but an assessment of its full utility in an ASD group has not been performed. We used WGS to examine 32 families with ASD to detect de novo or rare inherited genetic variants predicted to be deleterious (loss-of-function and damaging missense mutations). Among ASD probands, we identified deleterious de novo mutations in six of 32 (19%) families and X-linked or autosomal inherited alterations in ten of 32 (31%) families (some had combinations of mutations). The proportion of families identified with such putative mutations was larger than has been previously reported; this yield was in part due to the comprehensive and uniform coverage afforded by WGS. Deleterious variants were found in four unrecognized, nine known, and eight candidate ASD risk genes. Examples include CAPRIN1 and AFF2 (both linked to FMR1, which is involved in fragile X syndrome), VIP (involved in social-cognitive deficits), and other genes such as SCN2A and KCNQ2 (linked to epilepsy), NRXN1, and CHD7, which causes ASD-associated CHARGE syndrome. Taken together, these results suggest that WGS and thorough bioinformatic analyses for de novo and rare inherited mutations will improve the detection of genetic variants likely to be associated with ASD or its accompanying clinical symptoms.

Outcome, prognosis, and risk in a longitudinal follow-up study.

This study reports the results of a 4-year follow-up of a community sample of children who were ages 4 to 12 in 1983 at the first wave of data collection. Results on outcomes revealed that conduct disorder showed the greatest stability especially from late childhood to early adolescence. In multivariate analyses, both family dysfunction and problems getting along with others significantly predicted the persistence of one or more psychiatric disorders 4 years later, and low income predicted one or more psychiatric disorders among children free of disorder 4 years earlier. The implications of the results for the child psychiatric field, especially prevention, are discussed.