Prevalence and phenotypic impact of rare potentially damaging variants in autism spectrum disorder

Abstract

Background The Autism Sequencing Consortium identified 102 high-confidence autism spectrum disorder (ASD) genes, showing that individuals with ASD and with potentially damaging single nucleotide variation (pdSNV) in these genes had lower cognitive levels and delayed age at walking, when compared to ASD participants without pdSNV. Here, we made use of a Swedish sample of individuals with ASD (called PAGES, for Population-Based Autism Genetics & Environment Study) to evaluate the frequency of pdSNV and their impact on medical and psychiatric phenotypes, using an epidemiological frame and universal health reporting. We then combine findings with those for potentially damaging copy number variation (pdCNV). Methods SNV and CNV calls were generated from whole-exome sequencing and chromosome microarray data, respectively. Birth and medical register data were used to collect phenotypes. Results Of 808 individuals assessed by sequencing, 69 (9%) had pdSNV in the 102 ASC genes, and 144 (18%) had pdSNV in the 102 ASC genes or in a larger set of curated neurodevelopmental genes (from the Deciphering Developmental Disorders study, the gene2phenotype database, and the Radboud University gene lists). Three or more individuals had pdSNV in GRIN2B, POGZ, SATB1, DYNC1H1, SCN8A, or CREBBP. In comparison, out of the 996 individuals from whom CNV were called, 105 (11%) carried one or more pdCNV, including four or more individuals with CNV in the recurrent 15q11q13, 22q11.2, and 16p11.2 loci. Carriers of pdSNV were more likely to have intellectual disability (ID) and epilepsy, while carriers of pdCNV showed increased rates of congenital anomalies and scholastic skill disorders. Carriers of either pdSNV or pdCNV were more likely to have ID, scholastic skill disorders, and epilepsy. Limitations The cohort only included individuals with autistic disorder, the more severe form of ASD, and phenotypes are defined from medical registers. Not all genes studied are definitively ASD genes, and we did not have de novo information to aid in classification. Conclusions In this epidemiological sample, rare pdSNV were more common than pdCNV and the combined yield of potentially damaging variation was substantial at 27%. The results provide compelling rationale for the use of high-throughout sequencing as part of routine clinical workup for ASD and support the development of precision medicine in ASD.

Phenotypic Impact of Rare Potentially Damaging Copy Number Variation in Obsessive-Compulsive Disorder and Chronic Tic Disorders

“…We analyzed data from a large population-based epidemiological study in Sweden to evaluate the population characteristics of potentially damaging copy number variation in OCD and CTD. We identified potentially damaging variation in 9% of the OCD probands and 8% of the CTD probands, lower than other neurodevelopmental such as ASD [ 46 ]. The rate of pdCNV occurring within loci associated with known genomic disorders in our analysis was ~1%, somewhat lower than that reported in prior studies (1.5–3%) [ 31 , 33 ].…”

“…For regions with discrepant classifications between the two databases, we used the ClinGen classification. The final list included 95 regions ( Table S1 ) [ 46 ].…”

Gene-based therapeutics for rare genetic neurodevelopmental psychiatric disorders

“…As more genes for autism are discovered, the yield will likely increase. Adapted from Mahjani et al 18 tent, which enhances transgene stability by reducing immunogenicity. 50,51 Where possible, the availability of relevant pre-clinical models is key to study efficacy and safety.…”

“…[13][14][15] Studies to date confirm that common and rare variation appear to act additively in ASD. 16,17 Importantly, the diagnostic yield of exome sequencing in identifying such variants is very high, 18 leading to several recent papers recommending that exome sequencing be a first-line genetic test offered to those with ASD. 19,20 As sequencing continues in ASD, it is becoming possible to map the mechanisms associated with various gene mutations.…”

Reconsidering animal models used to study autism spectrum disorder: Current state and optimizing future

“…Animal models with the strongest construct validity are currently the high confidence risk genetic models. While ASD etiology is multi‐factorial, making construct validity “slippery” at times, 26 these high confidence rare genetic variants may contribute up to 27% of ASD risk 27 . Now that soon we model nearly a third of ASD with strong construct validity, the field is in critical need of a re‐examination of the way behavioral assays are used, interpreted and the findings reported.…”