Mapping autism risk loci using genetic linkage and chromosomal rearrangements.

Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,181 [corrected] families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs.

Rare deletions at the neurexin 3 locus in autism spectrum disorder.

The three members of the human neurexin gene family, neurexin 1 (NRXN1), neurexin 2 (NRXN2), and neurexin 3 (NRXN3), encode neuronal adhesion proteins that have important roles in synapse development and function. In autism spectrum disorder (ASD), as well as in other neurodevelopmental conditions, rare exonic copy-number variants and/or point mutations have been identified in the NRXN1 and NRXN2 loci. We present clinical characterization of four index cases who have been diagnosed with ASD and who possess rare inherited or de novo microdeletions at 14q24.3-31.1, a region that overlaps exons of the alpha and/or beta isoforms of NRXN3. NRXN3 deletions were found in one father with subclinical autism and in a carrier mother and father without formal ASD diagnoses, indicating issues of penetrance and expressivity at this locus. Notwithstanding these clinical complexities, this report on ASD-affected individuals who harbor NRXN3 exonic deletions advances the understanding of the genetic etiology of autism, further enabling molecular diagnoses.

Concordance of Diagnosis of Autism Spectrum Disorder Made by Pediatricians vs a Multidisciplinary Specialist Team.

Importance: Wait times for autism spectrum disorder (ASD) diagnosis are lengthy because of inadequate supply of specialist teams. General pediatricians may be able to diagnose some cases of ASD, thereby reducing wait times. Objective: To determine the accuracy of ASD diagnostic assessments conducted by general pediatricians compared with a multidisciplinary team (MDT). Design, Setting, and Participants: This prospective diagnostic study was conducted in and a specialist assessment center in Toronto, Ontario, Canada, and Ontario general pediatrician practices from June 2016 to March 2020. Children were younger than 5.5 years, referred with a developmental concern, and without an existing ASD diagnosis. Data analysis was performed from October 2021 to February 2022. Exposures: The pediatrician and MDT each conducted blinded assessments and recorded a decision as to whether the child had ASD. Main Outcomes and Measures: Main outcomes included sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). A logistic regression was performed to identify factors associated with accurate pediatrician assessment for children with or without an ASD diagnosis. Results: Seventeen pediatricians (12 women [71%]) participated in the study and referred 106 children (79 boys [75%]; mean [SD] age, 41.9 [13.3] months). Sixty participants (57%) were from minoritized racial and ethnic groups (eg, Black, Asian, Hispanic, Middle Eastern, and multiracial). Seventy-two participants (68%) received a diagnosis of ASD by the MDT. Sensitivity and specificity of the pediatrician assessments compared with MDT were 0.75 (95% CI, 0.67-0.83) and 0.79 (95% CI, 0.62-0.91), respectively. The PPV of the pediatrician assessments was 0.89 (95% CI, 0.80-0.94) (ie, 89% agreement with the MDT), and NPV was 0.60 (95% CI, 0.49-0.70) (ie, 60% agreement with the MDT). Higher pediatrician certainty (odds ratio [OR], 3.33; 95% CI, 1.71-7.34; P = .001) was associated with increased diagnostic accuracy for children with ASD. Lower accuracy was seen for children with higher Visual Reception subscale developmental skills (OR, 0.93; 95% CI, 0.89-0.97; P = .001), speaking abilities (OR, 0.17; 95% CI, 0.03-0.67; P = .03), and White race (OR, 0.32; 95% CI, 0.10-0.97; P = .04). Age, gender, and Autism Diagnostic Observation Schedule, 2nd Edition composite scores were not significantly associated with the accuracy of assessments. All 7 children with a sibling with ASD received an accurate diagnosis; otherwise, no significant factors were identified for accuracy in children without ASD. Conclusions and Relevance: This study of concordance of autism assessment between pediatricians and an expert MDT in young children found high accuracy when general pediatricians felt confident and lower accuracy when ruling out ASD. These findings suggest that children with co-occurring delays may be potential candidates for community assessment.

Understanding the Use of the Term "Weaponized Autism" in An Alt-Right Social Media Platform.

BACKGROUND: The term "weaponized autism" is frequently used on extremist platforms. To better understand this, we conducted a discourse analysis of posts on Gab, an alt-right social media platform. METHODS: We analyzed 711 posts spanning 2018-2019 and filtered for variations on the term "weaponized autism". RESULTS: This term is used mainly by non-autistic Gab users. It refers to exploitation of perceived talents and vulnerabilities of "Weaponized autists", described as all-powerful masters-of-technology who are devoid of social skills. CONCLUSIONS: The term "weaponized autism" is simultaneously glorified and derogatory. For some autistic people, the partial acceptance offered within this community may be preferable to lack of acceptance offered in society, which speaks to improving societal acceptance as a prevention effort.

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.

Disruption at the PTCHD1 Locus on Xp22.11 in Autism spectrum disorder and intellectual disability.

Autism is a common neurodevelopmental disorder with a complex mode of inheritance. It is one of the most highly heritable of the complex disorders, although the underlying genetic factors remain largely unknown. Here, we report mutations in the X-chromosome PTCHD1 (patched-related) gene in seven families with autism spectrum disorder (ASD) and in three families with intellectual disability. A 167-kilobase microdeletion spanning exon 1 was found in two brothers, one with ASD and the other with a learning disability and ASD features; a 90-kilobase microdeletion spanning the entire gene was found in three males with intellectual disability in a second family. In 900 probands with ASD and 208 male probands with intellectual disability, we identified seven different missense changes (in eight male probands) that were inherited from unaffected mothers and not found in controls. Two of the ASD individuals with missense changes also carried a de novo deletion at another ASD susceptibility locus (DPYD and DPP6), suggesting complex genetic contributions. In additional males with ASD, we identified deletions in the 5' flanking region of PTCHD1 that disrupted a complex noncoding RNA and potential regulatory elements; equivalent changes were not found in male control individuals. Thus, our systematic screen of PTCHD1 and its 5' flanking regions suggests that this locus is involved in ~1% of individuals with ASD and intellectual disability.

Speech and language impairment and oromotor dyspraxia due to deletion of 7q31 that involves FOXP2.

We report detailed clinical, cytogenetic, and molecular findings in a girl with a deletion of chromosome 7q31-q32. This child has a severe communication disorder with evidence of oromotor dyspraxia, dysmorphic features, and mild developmental delay. She is unable to cough, sneeze, or laugh spontaneously. Her deletion is on the paternally inherited chromosome and includes the FOXP2 gene, which has recently been associated with speech and language impairment and a similar form of oromotor dyspraxia in at least three other published cases. We hypothesize that our patient's communication disorder and oromotor deficiency are due to haploinsufficiency for FOXP2 and that her dysmorphism and developmental delay are a consequence of the absence of the other genes involved in the microdeletion. We propose that this patient, together with others reported in the literature, may define a new contiguous gene deletion syndrome encompassing the 7q31-FOXP2 region. Cytogenetic and molecular analysis of this region should be considered for other individuals displaying similar characteristics.

Absence of a paternally inherited FOXP2 gene in developmental verbal dyspraxia.

Mutations in FOXP2 cause developmental verbal dyspraxia (DVD), but only a few cases have been described. We characterize 13 patients with DVD--5 with hemizygous paternal deletions spanning the FOXP2 gene, 1 with a translocation interrupting FOXP2, and the remaining 7 with maternal uniparental disomy of chromosome 7 (UPD7), who were also given a diagnosis of Silver-Russell Syndrome (SRS). Of these individuals with DVD, all 12 for whom parental DNA was available showed absence of a paternal copy of FOXP2. Five other individuals with deletions of paternally inherited FOXP2 but with incomplete clinical information or phenotypes too complex to properly assess are also described. Four of the patients with DVD also meet criteria for autism spectrum disorder. Individuals with paternal UPD7 or with partial maternal UPD7 or deletion starting downstream of FOXP2 do not have DVD. Using quantitative real-time polymerase chain reaction, we show the maternally inherited FOXP2 to be comparatively underexpressed. Our results indicate that absence of paternal FOXP2 is the cause of DVD in patients with SRS with maternal UPD7. The data also point to a role for differential parent-of-origin expression of FOXP2 in human speech development.

Executive processes in appearance-reality tasks: the role of inhibition of attention and symbolic representation.

Two studies addressed the role of representation ability and control of attention on solutions to an appearance-reality task based on two types of objects, real and representational. In Study 1, 67 preschool children (3-, 4-, and 5-year-olds) solved appearance-reality problems and executive processing tasks. There was an interaction between object type (real vs. representational) and question type (appearance vs. reality) on problem difficulty. In addition, representational ability predicted performance on appearance questions and inhibitory control predicted performance on reality questions. In Study 2, 95 children (4- and 5-year-olds) who were monolingual or bilingual solved similar problems. On appearance questions, groups performed equivalently but on reality questions, bilinguals performed better (once language proficiency had been controlled). The difference is attributed to the advanced inhibitory control that comes with bilingualism.