OBJECTIVE:

The recurrence risk of autism spectrum disorders (ASD) is estimated to be between 3% and 10%, but previous research was limited by small sample sizes and biases related to ascertainment, reporting, and stoppage factors. This study used prospective methods to obtain an updated estimate of sibling recurrence risk for ASD.

METHODS:

A prospective longitudinal study of infants at risk for ASD was conducted by a multisite international network, the Baby Siblings Research Consortium. Infants (n = 664) with an older biological sibling with ASD were followed from early in life to 36 months, when they were classified as having or not having ASD. An ASD classification required surpassing the cutoff of the Autism Diagnostic Observation Schedule and receiving a clinical diagnosis from an expert clinician.

RESULTS:

A total of 18.7% of the infants developed ASD. Infant gender and the presence of >1 older affected sibling were significant predictors of ASD outcome, and there was an almost threefold increase in risk for male subjects and an additional twofold increase in risk if there was >1 older affected sibling. The age of the infant at study enrollment, the gender and functioning level of the infant's older sibling, and other demographic factors did not predict ASD outcome.

CONCLUSIONS:

The sibling recurrence rate of ASD is higher than suggested by previous estimates. The size of the current sample and prospective nature of data collection minimized many limitations of previous studies of sibling recurrence. Clinical implications, including genetic counseling, are discussed.

Background

Infants and preschoolers with ASD show impairment in their responses to other people's distress relative to children with other developmental delays and typically developing children. This deficit is expected to disrupt social interactions, social learning, and the formation of close relationships. Response to distress has not been evaluated previously in infants with ASD earlier than 18 months of age.

Methods

Participants were 103 infant siblings of children with autism and 55 low-risk controls. All children were screened for ASD at 36 months and 14 were diagnosed with ASD. Infants' responsiveness to distress was evaluated at 12, 18, 24, and 36 months. An examiner pretended to hit her finger with a toy mallet and infants' responses were video-recorded. Attention to the examiner and congruent changes in affect were coded on four-point Likert scales.

Results

Cross-sectional and longitudinal analyses confirm that the ASD group paid less attention and demonstrated less change in affect in response to the examiner's distress relative to the high-risk and low-risk participants who were not subsequently diagnosed with ASD. Group differences remained when verbal skills and general social responsiveness were included in the analytic models.

Conclusions

Diagnostic groups differ on distress response from 12 to 36 months of age. Distress-response measures are predictive of later ASD diagnosis above and beyond verbal impairments. Distress response is a worthwhile target for early intervention programs.

Longitudinal research into adult outcomes in autism remains limited. Unlike previous longitudinal examinations of adult outcome in autism, the twenty participants in this study were evaluated across multiple assessments between early childhood (M = 3.9 years) and adulthood (M = 26.6 years). In early childhood, responsiveness to joint attention (RJA), language, and intelligence were assessed. In adulthood, the parents of participants responded to interviews assessing the adaptive functioning, autistic symptomology and global functioning of their children. RJA and early childhood language predicted a composite measure of adult social functioning and independence. Early childhood language skills and intelligence predicted adult adaptive behaviors. RJA predicted adult non-verbal communication, social skills and symptoms. Adaptive behaviors changed with development, but symptoms of autism did not. Additional factors associated with adult outcomes are discussed.

Autism spectrum disorders (ASDs) represent a group of childhood neurodevelopmental and neuropsychiatric disorders characterized by deficits in verbal communication, impairment of social interaction, and restricted and repetitive patterns of interests and behaviour. To identify common genetic risk factors underlying ASDs, here we present the results of genome-wide association studies on a cohort of 780 families (3,101 subjects) with affected children, and a second cohort of 1,204 affected subjects and 6,491 control subjects, all of whom were of European ancestry. Six single nucleotide polymorphisms between cadherin 10 (CDH10) and cadherin 9 (CDH9)—two genes encoding neuronal cell-adhesion molecules—revealed strong association signals, with the most significant SNP being rs4307059 (P = 3.4 × 10−8, odds ratio = 1.19). These signals were replicated in two independent cohorts, with combined P values ranging from 7.4 × 10−8 to 2.1 × 10−10. Our results implicate neuronal cell-adhesion molecules in the pathogenesis of ASDs, and represent, to our knowledge, the first demonstration of genome-wide significant association of common variants with susceptibility to ASDs.

Objective

To examine prospectively the emergence of behavioral signs of autism in the first years of life in infants at low and high risk for autism.

Method

A prospective longitudinal design was used to compare 25 infants later diagnosed with an autism spectrum disorder (ASD) with 25 gender-matched low-risk children later determined to have typical development. Participants were evaluated at 6, 12, 18, 24, and 36 months of age. Frequencies of gaze to faces, social smiles, and directed vocalizations were coded from video and rated by examiners.

Results

The frequency of gaze to faces, shared smiles, and vocalizations to others were highly comparable between groups at 6 months of age, but significantly declining trajectories over time were apparent in the group later diagnosed with ASD. Group differences were significant by 12 months of age on most variables. Although repeated evaluation documented loss of skills in most infants with ASD, most parents did not report a regression in their child’s development.

Conclusions

These results suggest that behavioral signs of autism are not present at birth, as once suggested by Kanner, but emerge over time through a process of diminishment of key social communication behaviors. More children may present with a regressive course than previously thought, but parent report methods do not capture this phenomenon well. Implications for onset classification systems and clinical screening are also discussed.

Objective

To study the relationship between parent concerns about development in the first year and a half of life and later autism diagnostic outcomes.

Method

Parent concerns about development were collected for infants at high and low risk for autism, using a prospective, longitudinal design. Parents were asked about developmental concerns at study intake and when their infant was 6, 12, and 18 months. Infants were then followed up until 36 months, when diagnostic status was determined.

Results

By the time their child was 12 months, parents who have an older child with autism reported significantly more concerns in autism spectrum disorders-related areas than parents of children with typical outcomes. These concerns were significantly related to independent measures of developmental status and autism symptoms and helped predict which infants would later be diagnosed with autism or autism spectrum disorders. At 6 months, however, the concerns of parents who have an older child with autism do not predict outcome well.

Conclusion

Explicitly probing for parent concerns about development is useful for identifying children in need of closer monitoring and surveillance, as recommended by the American Academy of Pediatrics.

We investigated whether deficits in social gaze and affect and in joint attention behaviors are evident within the first year of life among siblings of children with autism who go on to be diagnosed with autism or ASD (ASD) and siblings who are non-diagnosed (NoASD-sib) compared to low-risk controls. The ASD group did not differ from the other two groups at 6 months of age in the frequency of gaze, smiles, and vocalizations directed toward the caregiver, nor in their sensitivity to her withdrawal from interaction. However, by 12 months, infants in the ASD group exhibited lower rates of joint attention and requesting behaviors. In contrast, NoASD-sibs did not differ from comparison infants on any variables of interest at 6 and 12 months.

We observed infant siblings of children with autism later diagnosed with ASD (ASD siblings; n = 17), infant siblings of children with autism with and without other delays (Other Delays and No Delays siblings; n = 12 and n = 19, respectively) and typically developing controls (TD controls; n = 19) during a free-play task at 18 months of age. Functional, symbolic, and repeated play actions were coded. ASD siblings showed fewer functional and more non-functional repeated play behaviors than TD controls. Other Delays and No Delays siblings showed more non-functional repeated play than TD controls. Group differences disappeared with the inclusion of verbal mental age. Play as an early indicator of autism and its relationship to the broader autism phenotype is discussed.

The genetics underlying the autism spectrum disorders (ASDs) is complex and remains poorly understood. Previous work has demonstrated an important role for structural variation in a subset of cases, but has lacked the resolution necessary to move beyond detection of large regions of potential interest to identification of individual genes. To pinpoint genes likely to contribute to ASD etiology, we performed high density genotyping in 912 multiplex families from the Autism Genetics Resource Exchange (AGRE) collection and contrasted results to those obtained for 1,488 healthy controls. Through prioritization of exonic deletions (eDels), exonic duplications (eDups), and whole gene duplication events (gDups), we identified more than 150 loci harboring rare variants in multiple unrelated probands, but no controls. Importantly, 27 of these were confirmed on examination of an independent replication cohort comprised of 859 cases and an additional 1,051 controls. Rare variants at known loci, including exonic deletions at NRXN1 and whole gene duplications encompassing UBE3A and several other genes in the 15q11–q13 region, were observed in the course of these analyses. Strong support was likewise observed for previously unreported genes such as BZRAP1, an adaptor molecule known to regulate synaptic transmission, with eDels or eDups observed in twelve unrelated cases but no controls (p = 2.3×10−5). Less is known about MDGA2, likewise observed to be case-specific (p = 1.3×10−4). But, it is notable that the encoded protein shows an unexpectedly high similarity to Contactin 4 (BLAST E-value = 3×10−39), which has also been linked to disease. That hundreds of distinct rare variants were each seen only once further highlights complexity in the ASDs and points to the continued need for larger cohorts.

Author Summary

Autism spectrum disorders (ASDs) are common neurodevelopmental syndromes with a strong genetic component. ASDs are characterized by disturbances in social behavior, impaired verbal and nonverbal communication, as well as repetitive behaviors and/or a restricted range of interests. To identify genes likely to contribute to ASD etiology, we performed high density genotyping in 912 multiplex families from the Autism Genetics Resource Exchange (AGRE) collection and contrasted results to those obtained for 1,488 healthy controls. To enrich for variants most likely to interfere with gene function, we restricted our analyses to deletions and gains encompassing exons. Of the many genomic regions highlighted, 27 were seen to harbor rare variants in cases and not controls, both in the first phase of our analysis, and also in an independent replication cohort comprised of 859 cases and 1,051 controls. More work in a larger number of individuals will be required to determine which of the rare alleles highlighted here are indeed related to the ASDs and how they act to shape risk.