Insights into autism spectrum disorder genomic architecture and biology from 71 risk loci

If the clinical population is constrained to those with ASD who are female or who have intellectual disability, multiple unaffected siblings or seizures, ~20-30% have a rare de novo mutation.

“If the clinical population is constrained to those with ASD who are female or who have intellectual disability, multiple unaffected siblings or seizures, ~20-30% have a rare de novo mutation [Au: edits for clarity based on Matt's comment, ok?] 34 .”

More than 100 genes and genomic regions have now been confidently associated with ASD, mostly based on the study of heterozygous, germline, de novo mutations.

“More than 100 genes and genomic regions have now been confidently associated with ASD 34,35 , mostly based on the study of heterozygous, germline, de novo mutations.”

Conservative estimates are that 10-20% of people with ASD harbour a de novo rare point mutation or CNV contributing to their presentation.

“Conservative estimates are that 10 -20% of people with ASD harbour a de novo rare point mutation or CNV contributing to their presentation (34, 49,50).”

Efforts aimed at the highest confidence risk genes identified in idiopathic ASD, such as SCN2A and CHD8, are almost certain to soon follow on attempts at gene therapy for monogenic neurodevelopmental disorders.

“Efforts aimed at the highest confidence risk genes identified in idiopathic ASD, such as SCN2A and CHD8 34,35 , are almost certain to soon follow on attempts at gene therapy for monogenic neurodevelopmental disorders”

Rare inherited and de novo variants are major contributors to individual risk for ASD.

“Rare inherited and de novo variants are major contributors to individual risk for autism spectrum disorder (ASD)”

The yield of de novo structural and sequence variations contributing to ASD is nearly double in girls than in boys.

“For example, the yield of de novo structural and sequence variations contributing to ASD is nearly double in girls than in boys (34).”

Past analyses have identified two major groups of ASD-associated genes: those involved in gene expression regulation (GER) and those involved in neuronal communication (NC).

“Past analyses have identified two major groups of ASD-associated genes: those involved in gene expression regulation (GER) and those involved in neuronal communication (NC) (De Rubeis et al., 2014; Sanders et al., 2015).”

In addition to GWAS, studies have begun to uncover rare genetic variants, such as copy number variants or protein truncating mutations, especially in ASD, which should be assessed as possible diagnostic biomarkers.

“It should be also considered that, in addition to GWAS, studies have begun to uncover rare genetic variants, such as copy number variants or protein truncating mutations, especially in ASD 67,68 , which should be assessed as possible diagnostic biomarkers.”

Autistic females are more likely to have high-impact de novo variants than autistic males.

“Autistic females are more likely to have high-impact de novo variants than autistic males17,26,46,47”

Females with ASD have a greater burden of rare CNVs and gene mutations than males with ASD.

“This hypothesis is supported by previous studies showing that females with ASD have a greater burden of rare CNVs1,11,12 and gene mutations13,14.”

Genetic studies of de novo variants have consistently supported a female protective effect against ASD.

“The possibility of a “female protective effect” (FPE) against ASD has been described extensively and has received consistent support from the results of genetic studies of de novo variants.4, 5, 6, 7, 8, 9, 10, 11, 12, 13”

Many types of ASD-associated de novo variants are observed more frequently in female cases.

“Many types of ASD-associated de novo variants are observed more frequently in female cases.4, 5, 6, 7, 8, 9, 10, 11, 12, 13”

Previously described differences in rare variant burden, along with preliminary evidence from studies of SNP heritability, already violate the assumption of equivalent genetic architecture between male ASD and female ASD.

“The previously described differences in rare variant burden, along with preliminary evidence from studies of SNP heritability, already violate that assumption.5, 6, 7, 8,15”

dnCNVs in female cases affect more genes than dnCNVs in males (2.3 vs 0.47 genes per female proband vs per male proband; p-value = 0.013).

“Similar to Sanders et al.8 dnCNVs in female cases also affect more genes than dnCNVs in males (2.3 vs 0.47 genes in dnCNVs per female proband vs per male proband, respectively; p-value = 0.013, Kruskal–Wallis test).”

MBD5 and IRF2BPL reached an FDR value of ≤0.1 in a previous meta-analysis but were not significant in this analysis of published de novo variants, because the previous study also included de novo CNVs and deleterious variants of unknown inheritance from a case-control sample.

“MBD5 and IRF2BPL reached an FDR value of ≤0.1 in a previous meta-analysis but not significant in our analysis of published de novo variants,8 because the previous study also included evidence from de novo CNVs and deleterious variants of unknown inheritance from a case-control sample in that analysis.”

ASD individuals have two- to three-fold more rare CNVs and de novo loss-of-function variants than unaffected siblings.

“individuals with ASD have a two- to three-fold increase in the number of rare copy number variations (CNVs) and de novo loss-of-function (nonsense, frameshift, and splice site) variants compared to their unaffected siblings11–14.”

Over 100 genes and loci are known to increase ASD likelihood.

“more than 100 genes and loci are known to be associated with increased likelihood of ASD2,13.”

ASD-associated genes including ARX, SCN1A, GABRB3, CNTNAP2, and possibly CNTNAP4 illustrate the importance of E:I coordination.

“Taken together with other genes (e.g., GABRB3, CNTNAP2 (Sanders et al., 2015), and possibly CNTNAP4 (Karayannis et al. 2014)), these ASD-associated genes illustrate the importance of E:I coordination.”

Both rare missense and inherited mutations contribute to autism spectrum disorder, with smaller effect sizes than de novo variants.

“both rare missense and inherited mutations have been shown to contribute to ASD, simply with smaller effect sizes than de novo variants (Ruzzo et al., 2018; Sanders et al., 2015)”

Applying TADA to exomes or whole genomes in large family samples is the most effective strategy for identifying ASD susceptibility genes.

“The application of this approach to exomes or whole genomes in large family samples has since become the most effective strategy for identifying ASD susceptibility genes (De Rubeis et al., 2014; Iossifov et al., 2014; Sanders et al., 2015; Satterstrom et al., 2018).”

Sanders et al. found no increased rate of de novo protein-truncating mutations inside large CNVs containing more than seven genes, but a significantly increased rate within smaller CNVs.

“Sanders et al. examined rates of gene mutations within large CNVs and without and found no evidence for an increased rate of de novo protein truncation mutations inside of large CNVs that contained >7 genes, whereas there was a significantly increased rate of de novo mutation within smaller CNVs (Sanders et al., 2015).”

ANK2 is an autism spectrum disorder risk gene.

“the ASD risk gene ANK2 (81)”

FOXP1 has been implicated in ASD aetiology based on observations of multiple de novo SNVs.

“FOXP1, a member of the Forkhead Box P family of transcription factors has been implicated in ASD aetiology based on observations of multiple de novo SNVs [65–67].”