GoKawiilPhenotype–genotype analysis
Ethics statement
This research involving human participants complies with all relevant ethical regulations, including obtaining informed consent from all participants through the recruitment sites. Ethical review and approval were obtained from The Hospital for Sick Children Research Ethics Board (REB 1000080561).
ASD-associated genetic variants at the PTCHD1-PTCHD1-AS locus in ASD cohorts
We analysed MSSNG, Simons Simplex Cohort and SPARK ASD WGS databases for genomic variants at the PTCHD1-PTCHD1-AS locus, with ethics approval and informed consent for the MSSNG database as previously described4,51. MSSNG cohorts contain family data with at least one child having a diagnosis of ASD. Rare microdeletion variants are defined as those less than 1 Mb in size and occur at a frequency of below 1% in control population cohorts. Variants meeting these criteria are then evaluated for ASD risk, and corresponding phenotype data are collected.
Frequency impact of rare deletions across the PTCHD1-PTCHD1-AS locus
We conducted a comparative analysis of the frequency of rare copy-number deletions (populational frequency less than 1%) overlapping the target exons on PTCHD1-AS, as well as PTCHD1 and DDX53. We assessed deletions with a length of 1 kb or more, identified as previously described52 across three independent ASD cohorts (MSSNG, SSC, and SPARK)4,15,53, contrasting with six independent control cohorts (1000 Genomes Project, 1,234 male individuals54; MGRB, 1,756 male individuals55,56; HostSeq, 4,235 male individuals57; CHILD, 203 male individuals58; INOVA, 100 male individuals, www.inova.org); cardiomyopathy59 and congenital heart disease cohorts, 804 male individuals60). Our analysis exclusively considered high-quality deletions, meeting the following criteria: (1) length of at least 1 kb; (2) identification by both ERDS61 and CNVnator62, with at least 50% reciprocal overlap between the two methods; (3) less than 70% overlap with repetitive or low complexity genomic regions (such as telomeres, centromeres and segmental duplications); (4) exclusion of CNVs in the pseudoautosomal regions or X chromosomal calls in males. We then used Fisher’s exact tests to compare the occurrence of overlapping deletions in male individuals within each target region between probands and control cohorts, resulting in final P values and ORs. The final comparison includes all PTCHD1-AS from exons 2 to 5, including the novel exons. We also analysed deletions overlapping DDX53 and PTCHD1 for comparison purposes.
Analysis of genotype–phenotype relationship in NDD cohorts at the PTCHD1-PTCHD1-AS locus
In ASD-specific cohorts with WGS data or any technology and primary diagnosis of ASD, individual data from the publicly available database DECIPHER v.11.27 and Lineagen (a private genetic diagnostic company) were accessed in September 2024 and February 2017, respectively. The individual selection and cohort descriptions are summarized in Supplementary Table 18. Here the primary diagnosis is the main NDD. Secondary diagnoses may include other disorders (such as ADHD, ADD, obsessive–compulsive disorder), other neurological conditions (epilepsy, presence of seizures) or additional mental health conditions (anxiety). Records of each database were obtained first by searching for PTCHD1-AS or PTCHD1 loss of function genetic variants in all databases or published cohorts.
Mouse models
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