eP287: Return of individual genetic results in the largest recontactable cohort of individuals with autism

SPARK (SPARKforAutism.org)—the largest recontactable cohort of people with autism spectrum disorder (ASD)—seeks to engage at least 50,000 individuals with autism and their family members in research. A tenet of the study is to form a partnership with participants and return research results to them. As part of this goal, SPARK returns ACMG likely pathogenic (LP) and pathogenic (P) variants from a predefined list of 167 high-confidence ASD genes and 43 copy number variants (CNVs) as well as developmental disorder genes curated by the Developmental Disorder Genotype - Phenotype Database (DDG2P). All variants for return are confirmed in a CLIA (Clinical Laboratory Improvement Amendments) laboratory. All inherited, autosomal dominant, returnable SNVs (single nucleotide variants) are rare (AF < 1 x 10-6, non-neuro gnomAD v2.1) or recurrent and already interpreted in ClinVar as P/LP with no conflicts. At the time of enrollment, each participant sets preferences to accept or decline to receive genetic results related to autism and a guardian consents for children and dependent adults. Participants may receive their result from a genetic counselor (at no cost to them) or from their own healthcare provider. We have identified 1,711 returnable results in 21,149 participants with autism (8%). For ASD probands, 39% of results occurred de novo, 12% were inherited from a parent, 2% were recessive or hemizygous dominant transmitted from a mother to a son, and 47% of results were of undetermined inheritance. Results for return are 59% SNVs or indels with the remainder being chromosomal abnormalities or CNVs. The results show significant heterogeneity, with most genes or loci accounting for no more than 2% of results returned. The most common CNV is the 16p11.2 deletion in roughly 4% of results, and the most frequent gene is SCN2A in 2% of results. Other common CNVs include 16p11.2 duplications, 2p16.3 deletions, and 15q13.3 deletions. The top recurrent genes with SNVs include SHANK3, NF1, and PTEN. For 40% of participants with autism, SPARK has DNA from both parents and has a sample from one parent in an additional 14%. Diagnostic yield in offspring with two parents available is 9% compared with 7% for those with only one or no parent with DNA available. The odds of identifying a result for return is 1.4-fold higher if both parents submitted samples (p=3.1E-10). One hundred and one parents, of whom three endorsed an autism diagnosis, transmitted a P/LP CNV to a child with autism. 64 parents, of whom three endorsed a diagnosis of autism, transmitted a P/LP SNV. Thirty-five percent of parents who transmitted a P/LP SNV and 29% of those who transmitted a P/LP CNV endorsed another neuropsychiatric or autism-related symptom including bipolar disorder, attention deficit hyperactivity disorder (ADHD), schizophrenia, obsessive compulsive disorder, seizures, personality disorder, motor delay, social anxiety, learning delay, and cognitive impairment. The odds of a parent having one of these features is 2.2 times higher (than parents in SPARK who did not transmit) if they transmitted an SNV to a child with autism (p=0.009) and 1.7-fold higher if they transmitted a CNV (p=0.04). The neuropsychiatric condition most common in transmitting parents is ADHD. The odds of a parent having ADHD is 3.2 times higher if they transmitted an SNV to a child with autism (p=0.001) and 2.3-fold higher if they transmitted a CNV (p=0.004). Being a female with autism increases the odds of having an autism-related genetic result by 1.7-fold, compared with males (p=2.8E-22). The odds of having an autism-related genetic result is 2 to 3 times higher with any of the following: cognitive impairment, significant speech delay, congenital anomaly, motor delay, or seizures. By contrast, having depression or features of ADHD was not associated with a different likelihood of having an autism-related genetic result. The odds of having an autism-related genetic result in participants who are female with seizures, motor delay, and cognitive impairment are 6 times higher than males with none of these features (p=2.4E-15). The odds of having an autism-related genetic result are 0.28 times lower if the participant has above-average cognitive ability (p=2.3E-48), defined as a self- or parent-report of cognitive ability “above age level” or a cognitive test score of 110 or above. However, 3% of people with above-average cognitive ability have a genetic result, and 8% of participants with results reported no cognitive impairment, seizures, or motor delay. Eighty-five percent of families chose to receive their result from a SPARK-provided genetic counselor or investigator rather than their own medical provider. Reports from the genetic counselors indicate that 90% of participants found the return to be a “positive” experience, 9% were “indifferent,” and 1% provided no feedback. Our experiences demonstrate that it is possible to return genetic results to hundreds of individuals at scale and that an autism-related genetic result can be identified in just under 10% of individuals ascertained through a non-clinical cohort. Although syndromic features such as seizures or cognitive impairment increase the odds of finding a genetic result, the findings are not restricted to individuals with these features. Although having samples from both parents raises the odds of finding a returnable result, incremental yield is modest and suggests that complete families are not always necessary to provide relevant genetic information to individuals with autism.