Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes

Abstract

Purpose-To maximize the discovery of potentially pathogenic variants to better understand the diagnostic utility of genome sequencing (GS) and to assess how the presence of multiple risk events might affect the phenotypic severity in autism spectrum disorders (ASD). Methods-GS was applied to 180 simplex and multiplex ASD families (578 individuals, 213 patients) with exome sequencing and array comparative genomic hybridization further applied to a subset for validation and cross-platform comparisons. Results-We found that 40.8% of patients carried variants with evidence of disease risk, including a de novo frameshift variant in NR4A2 and two de novo missense variants in SYNCRIP, while 21.1% carried clinically relevant pathogenic or likely pathogenic variants. Patients with more than one risk variant (9.9%) were more severely affected with respect to cognitive ability compared with patients with a single or no-risk variant. We observed no instance among the 27

Phenotype‐to‐genotype approach reveals head‐circumference‐associated genes in an autism spectrum disorder cohort

“…The diagnostic yield (18%, 12/67) is 2-fold higher than the diagnostic yield (8.9%) among a recent larger unselected ASD cohorts when only considering the SNV/indels. 29…”

Hypogonadotrophic hypogonadism, delayed puberty and risk for neurodevelopmental disorders

“…Clinical genetic testing is recommended for individuals with ID and ASD . Currently, molecular diagnosis can be obtained for up to 50% of ID and ASD cases using chromosomal microarray and sequencing of the whole exome and genomes …”

“…12 Currently, molecular diagnosis can be obtained for up to 50% of ID and ASD cases using chromosomal microarray and sequencing of the whole exome and genomes. [13][14][15] The sex ratio of NDDs is skewed, with more boys being diagnosed than girls. Although the reasons for the unbalanced sex ratio remain unknown, it has been hypothesised that sex hormone dysregulation, especially elevated prenatal testosterone levels, increases the risk for ASD.…”

Recent ultra-rare inherited mutations identify novel autism candidate risk genes

“…We generated WGS data (30-fold sequence coverage) from 2,507 individual DNA samples from 394 multiplex and 251 simplex autism families (Table 1, table S1, and Materials and Methods). Combined with previously published WGS data (7,18,19), we created a standardized 15 callset of SNVs and indels from 13,547 genome samples using two callers and have made these publically available (Data and materials availability). The set consists of data from 4,364 probands and 2,235 siblings and includes parent-child SNV data from 774 multiplex and 2,700 simplex families.…”

“…We expand the number of multiplex and simplex autism families sequenced taking advantage of the increased sensitivity afforded by whole-genome sequencing (WGS) over whole-exome sequencing (WES) data (16) to create a highly sensitive LGD variant callset from WGS data from 3,474 simplex and multiplex autism families from the Centers for Common Disease Genomics (CCDG) ( Table 1 and table S1). We use these to assess transmission biases of this class of variant to probands and unaffected siblings after controlling for population structure (7,(17)(18)(19)(20). Further, we replicate these analyses in WES data from 5,879 families from the Simons Foundation Powering Autism Research Knowledge (SPARK) (21,22).…”