Brief Report: Associations Between Self-injurious Behaviors and Abdominal Pain Among Individuals with ASD-Associated Disruptive Mutations.

Self-injurious behaviors (SIB) are elevated in autism spectrum disorder (ASD) and related genetic disorders, but the genetic and biological mechanisms that contribute to SIB in ASD are poorly understood. This study examined rates and predictors of SIB in 112 individuals with disruptive mutations to ASD-risk genes. Current SIB were reported in 30% of participants and associated with poorer cognitive and adaptive skills. History of severe abdominal pain predicted higher rates of SIB and SIB severity after controlling for age and adaptive behavior; individuals with a history of severe abdominal pain were eight times more likely to exhibit SIB than those with no history. Future research is needed to examine associations between genetic risk, pain, and SIB in this population.

Co-occurring medical conditions among individuals with ASD-associated disruptive mutations.

Children with autism spectrum disorder (ASD) are at risk for co-occurring medical conditions, many of which have also been reported among individuals with mutations in ASD-associated genes. This study examined rates of co-occurring medical conditions across 301 individuals with disruptive mutations to 1 of 18 ASD-risk genes in comparison to rates of conditions in an idiopathic ASD sample. Rates of gastrointestinal problems, seizures, physical anomalies, and immune problems were generally elevated, with significant differences in rates observed between groups. Results may inform medical care of individuals with ASD-associated mutations and research into mechanisms of co-occurring medical conditions in ASD.

Clinical Phenotypes of Carriers of Mutations in CHD8 or Its Conserved Target Genes.

BACKGROUND: Variants disruptive to CHD8 (which codes for the protein CHD8 [chromodomain-helicase-DNA-binding protein 8]) are among the most common mutations revealed by exome sequencing in autism spectrum disorder (ASD). Recent work has indicated that CHD8 plays a role in the regulation of other ASD-risk genes. However, it is unclear whether a possible shared genetic ontology extends to the phenotype. METHODS: This study (N = 143; 42.7% female participants) investigated clinical and behavioral features of individuals ascertained for the presence of a known disruptive ASD-risk mutation that is 1) CHD8 (CHD8 group) (n = 15), 2) a gene targeted by CHD8 (target group) (n = 22), or 3) a gene without confirmed evidence of being targeted by CHD8 (other gene group) (n = 106). RESULTS: Results indicated shared features between the CHD8 and target groups that included less severe adaptive deficits in communication skills, similar functional language, more social motivation challenges in those with ASD, larger head circumference, higher weight, and lower seizure prevalence relative to the other gene group. CONCLUSIONS: These similarities suggest broader genetic ontology accounts for aspects of phenotypic heterogeneity. Improved understanding of the relationships between related disruptive gene events may lead us to improved understanding of shared mechanisms and lead to more focused treatments for individuals with known genetic mutations.

Auditory perception is associated with implicit language learning and receptive language ability in autism spectrum disorder.

BACKGROUND: Autism spectrum disorder (ASD) is associated with language impairment as well as atypical auditory sensory processing. The current study investigated associations among auditory perception, implicit language learning and receptive language ability in youth with ASD. METHODS: We measured auditory event related potentials (ERP) during an artificial language statistical learning task in 76 youth with ASD and 27 neurotypical (NT) controls. Participants with ASD had a broad range of cognitive and language abilities. RESULTS: NT youth showed evidence of implicit learning via attenuated P1 amplitude in the left hemisphere. In contrast, among youth with ASD, implicit learning elicited bilateral attenuation that was increasingly evident with greater receptive language skill. CONCLUSIONS: Efficient early auditory perception reflects language learning and is a marker of language ability among youth with ASD. Atypical lateralization of word learning is evident in ASD across a broad range of receptive language abilities.

The autism spectrum phenotype in ADNP syndrome.

Pathogenic disruptions to the activity-dependent neuroprotector homeobox (ADNP) gene are among the most common heterozygous genetic mutations associated with autism spectrum disorders (ASDs). Individuals with ADNP disruptions share a constellation of medical and psychiatric features, including ASD, intellectual disability (ID), dysmorphic features, and hypotonia. However, the profile of ASD symptoms associated with ADNP may differ from that of individuals with another ASD-associated single gene disruption or with ASD without a known genetic cause. The current study examined the ASD phenotype in a sample of representative youth with ADNP disruptions. Participants (N = 116, ages 4-22 years) included a cohort with ADNP mutations (n = 11) and three comparison groups with either a mutation to CHD8 (n = 11), a mutation to another ASD-associated gene (other mutation; n = 53), or ASD with no known genetic etiology (idiopathic ASD; n = 41). As expected, individuals with ADNP disruptions had higher rates of ID but less severe social affect symptoms compared to the CHD8 and Idiopathic ASD groups. In addition, verbal intelligence explained more variance in social impairment in the ADNP group compared to CHD8, other mutation, and idiopathic ASD comparison groups. Restricted and repetitive behaviors in the ADNP group were characterized by high levels of stereotyped motor behaviors, whereas the idiopathic ASD group showed high levels of restricted interests. Taken together, these results underscore the role of ADNP in cognitive functioning and suggest that social impairments in ADNP syndrome are consistent with severity of verbal deficits. Autism Res 2018, 11: 1300-1310. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Disruptions to the ADNP gene (i.e., ADNP syndrome) have been associated with autism spectrum disorder (ASD). This article describes intellectual disability, mild social difficulties, and severe repetitive motor movements in a group of 11 youth with ADNP Syndrome. We found lower rates of ASD than previously reported. Verbal skills explained individual variability in social impairment. This pattern suggests that the ADNP gene is primarily associated with learning and memory, and level of social difficulties is consistent with level of verbal impairment.

Longitudinal report of child with de novo 16p11.2 triplication.

16p11.2 deletions and duplications are commonly associated with autism spectrum disorder and linked to mirrored phenotypes of physical characteristics and higher penetrance for deletions. A male with a rare 16p11.2 triplication demonstrated a similar phenotypic presentation to deletion carriers with neurocognitive and adaptive skill deficits and above-average physical growth.

Comorbid symptoms of inattention, autism, and executive cognition in youth with putative genetic risk.

BACKGROUND: Symptoms of autism spectrum disorder (ASD) and inattention (IA) are highly comorbid and associated with deficits in executive cognition. Cognitive deficits have been posited as candidate endophenotypes of psychiatric traits, but few studies have conceptualized cognitive deficits as psychiatric comorbidities. The latter model is consistent with a latent factor reflecting broader liability to neuropsychological dysfunction, and explains heterogeneity in the cognitive profile of individuals with ASD and IA. METHODS: We tested competing models of covariance among symptoms of ASD, IA, and cognition in a sample of 73 youth with a known genetic mutation. RESULTS: A common executive factor fit best as a cognitive comorbidity, rather than endophenotype, of the shared variance between measures of IA and ASD symptoms. Known genetic risk explained a third of the shared variance among psychiatric and cognitive measures. CONCLUSIONS: Comorbid symptoms of ASD, IA, and cognitive deficits are likely influenced by common neurogenetic factors. Known genetic risk in ASD may inform future investigation of putative genetic causes of IA.

Prospective investigation of FOXP1 syndrome.

BACKGROUND: Haploinsufficiency of the forkhead-box protein P1 (FOXP1) gene leads to a neurodevelopmental disorder termed FOXP1 syndrome. Previous studies in individuals carrying FOXP1 mutations and deletions have described the presence of autism spectrum disorder (ASD) traits, intellectual disability, language impairment, and psychiatric features. The goal of the present study was to comprehensively characterize the genetic and clinical spectrum of FOXP1 syndrome. This is the first study to prospectively examine the genotype-phenotype relationship in multiple individuals with FOXP1 syndrome, using a battery of standardized clinical assessments. METHODS: Genetic and clinical data was obtained and analyzed from nine children and adolescents between the ages of 5-17 with mutations in FOXP1. Phenotypic characterization included gold standard ASD testing and norm-referenced measures of cognition, adaptive behavior, language, motor, and visual-motor integration skills. In addition, psychiatric, medical, neurological, and dysmorphology examinations were completed by a multidisciplinary team of clinicians. A comprehensive review of reported cases was also performed. All missense and in-frame mutations were mapped onto the three-dimensional structure of DNA-bound FOXP1. RESULTS: We have identified nine de novo mutations, including three frameshift, one nonsense, one mutation in an essential splice site resulting in frameshift and insertion of a premature stop codon, three missense, and one in-frame deletion. Reviewing prior literature, we found seven instances of recurrent mutations and another 34 private mutations. The majority of pathogenic missense and in-frame mutations, including all four missense mutations in our cohort, lie in the DNA-binding domain. Through structural analyses, we show that the mutations perturb amino acids necessary for binding to the DNA or interfere with the domain swapping that mediates FOXP1 dimerization. Individuals with FOXP1 syndrome presented with delays in early motor and language milestones, language impairment (expressive language > receptive language), ASD symptoms, visual-motor integration deficits, and complex psychiatric presentations characterized by anxiety, obsessive-compulsive traits, attention deficits, and externalizing symptoms. Medical features included non-specific structural brain abnormalities and dysmorphic features, endocrine and gastrointestinal problems, sleep disturbances, and sinopulmonary infections. CONCLUSIONS: This study identifies novel FOXP1 mutations associated with FOXP1 syndrome, identifies recurrent mutations, and demonstrates significant clustering of missense mutations in the DNA-binding domain. Clinical findings confirm the role FOXP1 plays in development across multiple domains of functioning. The genetic findings can be incorporated into clinical genetics practice to improve accurate genetic diagnosis of FOXP1 syndrome and the clinical findings can inform monitoring and treatment of individuals with FOXP1 syndrome.