Targeted sequencing and integrative analysis of 3,195 Chinese patients with neurodevelopmental disorders prioritized 26 novel candidate genes

Autism spectrum disorder trios from consanguineous populations are enriched for rare biallelic variants, identifying 32 new candidate genes

“…A number of the ID genes identified here among ASD trios have also previously been reported for ASD or ASD-like features, e.g. CC2D1A (Manzini et al, 2014;Sener et al, 2020), VPS13B (Yu et al, 2013), DEAF1 (Nabais Sá et al, 2019), ZNF335 (Wu et al, 2018), ZNF292 (Guo et al, 2018;Mirzaa et al, 2019;Wang et al, 2016), MYT1L (Coursimault et al, 2021;, SCN2A (Jiang et al, 2013;Sanders et al, 2012;Weiss et al, 2003), and PLXNA3 (Steele et al, 2021;Wang et al, 2021). Of the candidate genes identified here, MSSNG, SFARI, and other datasets provide putative support (however it is not possible to determine whether two reported mutations in the same gene are on the same alleles or not, unless occurring within the same sequence read) for the biallelic genes DNAH8, SCN10A, CLCA4, ANO10, WDR90 (Supplementary Table S1), and for de novo/dominant genes NCL, SLAMF7, ADGRF2, DGKZ, ATP2B1, CBFA2T3, RETN, and PPIL2 (Supplementary Table S2).…”

Semaphorin-Plexin Signaling: From Axonal Guidance to a New X-Linked Intellectual Disability Syndrome

“…However, the probability of loss-of-function intolerance (pLI ≥ 0.9) metric for PLXNA3 predicts a high level of constraint. [42] In addition, it is not known whether pregnancies in asymptomatic women carrying pathogenic loss-of-function variants lead to natural selection with higher rates of fetal loss (suggested by case report 2 in this study) or the reduction of such PLXNA3 variants in genetic studies of postnatally-diagnosed neurodevelopmental disorders such as autism/ID. Thus, it remains uncertain whether all of the maternally inherited hemizygous PLXNA3 missense variants in our cohort are unambiguously benign or deleterious.…”

Integrative analysis prioritised oxytocin-related biomarkers associated with the aetiology of autism spectrum disorder

“…To further explore the relationship between these high/low PC-OTRGs and ASD risk, 1,229 ASD genes consisting of 559 ASD core genes and the remaining 670 ASD-associated genes were collected from our previous NDD study, 68 SFARI, and AutDB databases ( Figure 3 c). We found that 36·66% of the high PC-OTRGs and 28·87% of the low PC-OTRGs ( Figure 3 d-e) were shared with ASD genes (32 ASD core and 20 ASD-associated genes; Supplemental Figure 4a, p = 1·16 × 10 −20 , hypergeometric test).…”

“…The permutation test was performed on the positively contributed OTRGs (PC-OTRGs) and the collected known ASD genes based on BrainSpain co-expression and PPI data to evaluate their functional connections. Similar to previous studies, 47 , 48 , 72 gene pairs co-expressed with | R | > 0·8 in the human brain 73 or PPI with a score > 400 in STRING or a score > 0·8 in InWeb_IM50, 74 were considered as connected. In brief, the numbers of connected genes within the 172 PC-OTRGs and the collected known ASD genes and their connections were compared with corresponding numbers produced by 172 random genes of 1,000,000 iterations, as in our previous study.…”

“…ASD genes identified by genetic variations were collected from the following three sources: (1) ASD candidates defined in our previous study on NDDs; 68 (2) genes retrieved from the Simons Foundation Autism Research Initiative (SFARI) database ( https://gene.sfari.org/ ); and (3) genes documented in the AutDB database. 59 Gene-level LoF intolerance (pLI) scores were downloaded from the Genome Aggregation Database (gnomAD) 69 (v2.2.1).…”