A Genetics-First Approach to Dissecting the Heterogeneity of Autism: Phenotypic Comparison of Autism Risk Copy Number Variants

Objective: Certain copy number variants (CNVs) greatly increase the risk of autism. The authors conducted a genetics-first study to investigate whether heterogeneity in the clinical presentation of autism is underpinned by specific genotype-phenotype relationships.

Methods: This international study included 547 individuals (mean age, 12.3 years [SD=4.2], 54% male) who were ascertained on the basis of having a genetic diagnosis of a rare CNV associated with high risk of autism (82 16p11.2 deletion carriers, 50 16p11.2 duplication carriers, 370 22q11.2 deletion carriers, and 45 22q11.2 duplication carriers), as well as 2,027 individuals (mean age, 9.1 years [SD=4.9], 86% male) with autism of heterogeneous etiology. Assessments included the Autism Diagnostic Interview-Revised and IQ testing.

Results: The four genetic variant groups differed in autism symptom severity, autism subdomain profile, and IQ profile. However, substantial variability was observed in phenotypic outcome in individual genetic variant groups (74%-97% of the variance, depending on the trait), whereas variability between groups was low (1%-21%, depending on the trait). CNV carriers who met autism criteria were compared with individuals with heterogeneous autism, and a range of profile differences were identified. When clinical cutoff scores were applied, 54% of individuals with one of the four CNVs who did not meet full autism diagnostic criteria had elevated levels of autistic traits.

Conclusions: Many CNV carriers do not meet full diagnostic criteria for autism but nevertheless meet clinical cutoffs for autistic traits. Although profile differences between variants were observed, there is considerable variability in clinical symptoms in the same variant.

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References

Hodapp R . Direct and indirect behavioral effects of different genetic disorders of mental retardation. Am J Ment Retard. 1997; 102(1):67-79. DOI: 10.1352/0895-8017(1997)102<0067:DAIBEO>2.0.CO;2. View

Kim S, Macari S, Koller J, Chawarska K . Examining the phenotypic heterogeneity of early autism spectrum disorder: subtypes and short-term outcomes. J Child Psychol Psychiatry. 2015; 57(1):93-102. PMC: 6852790. DOI: 10.1111/jcpp.12448. View

Gur R, Bassett A, McDonald-McGinn D, Bearden C, Chow E, Emanuel B . A neurogenetic model for the study of schizophrenia spectrum disorders: the International 22q11.2 Deletion Syndrome Brain Behavior Consortium. Mol Psychiatry. 2017; 22(12):1664-1672. PMC: 5935262. DOI: 10.1038/mp.2017.161. View

Niarchou M, Chawner S, Doherty J, Maillard A, Jacquemont S, Chung W . Psychiatric disorders in children with 16p11.2 deletion and duplication. Transl Psychiatry. 2019; 9(1):8. PMC: 6341088. DOI: 10.1038/s41398-018-0339-8. View

Schneider M, Debbane M, Bassett A, Chow E, Fung W, van den Bree M . Psychiatric disorders from childhood to adulthood in 22q11.2 deletion syndrome: results from the International Consortium on Brain and Behavior in 22q11.2 Deletion Syndrome. Am J Psychiatry. 2014; 171(6):627-39. PMC: 4285461. DOI: 10.1176/appi.ajp.2013.13070864. View

Klaassen P, Duijff S, Swanenburg de Veye H, Beemer F, Sinnema G, Breetvelt E . Explaining the variable penetrance of CNVs: Parental intelligence modulates expression of intellectual impairment caused by the 22q11.2 deletion. Am J Med Genet B Neuropsychiatr Genet. 2016; 171(6):790-6. DOI: 10.1002/ajmg.b.32441. View

Szatmari P, Georgiades S, Duku E, Bennett T, Bryson S, Fombonne E . Developmental trajectories of symptom severity and adaptive functioning in an inception cohort of preschool children with autism spectrum disorder. JAMA Psychiatry. 2015; 72(3):276-83. DOI: 10.1001/jamapsychiatry.2014.2463. View

Ronald A, Happe F, Bolton P, Butcher L, Price T, Wheelwright S . Genetic heterogeneity between the three components of the autism spectrum: a twin study. J Am Acad Child Adolesc Psychiatry. 2006; 45(6):691-699. DOI: 10.1097/01.chi.0000215325.13058.9d. View

Lord C, Veenstra-VanderWeele J . Following the Trail From Genotype to Phenotypes. JAMA Psychiatry. 2015; 73(1):7-8. DOI: 10.1001/jamapsychiatry.2015.2344. View

10.

Bruining H, Eijkemans M, Kas M, Curran S, Vorstman J, Bolton P . Behavioral signatures related to genetic disorders in autism. Mol Autism. 2014; 5(1):11. PMC: 3936826. DOI: 10.1186/2040-2392-5-11. View

11.

Pinto D, Delaby E, Merico D, Barbosa M, Merikangas A, Klei L . Convergence of genes and cellular pathways dysregulated in autism spectrum disorders. Am J Hum Genet. 2014; 94(5):677-94. PMC: 4067558. DOI: 10.1016/j.ajhg.2014.03.018. View

12.

Sanders S, Ercan-Sencicek A, Hus V, Luo R, Murtha M, Moreno-De-Luca D . Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron. 2011; 70(5):863-85. PMC: 3939065. DOI: 10.1016/j.neuron.2011.05.002. View

13.

Antshel K, Aneja A, Strunge L, Peebles J, Fremont W, Stallone K . Autistic spectrum disorders in velo-cardio facial syndrome (22q11.2 deletion). J Autism Dev Disord. 2006; 37(9):1776-86. DOI: 10.1007/s10803-006-0308-6. View

14.

Charman T, Pickles A, Simonoff E, Chandler S, Loucas T, Baird G . IQ in children with autism spectrum disorders: data from the Special Needs and Autism Project (SNAP). Psychol Med. 2011; 41(3):619-27. DOI: 10.1017/S0033291710000991. View

15.

Malhotra D, Sebat J . CNVs: harbingers of a rare variant revolution in psychiatric genetics. Cell. 2012; 148(6):1223-41. PMC: 3351385. DOI: 10.1016/j.cell.2012.02.039. View

16.

Kates W, Antshel K, Fremont W, Shprintzen R, Strunge L, Burnette C . Comparing phenotypes in patients with idiopathic autism to patients with velocardiofacial syndrome (22q11 DS) with and without autism. Am J Med Genet A. 2007; 143A(22):2642-50. DOI: 10.1002/ajmg.a.32012. View

17.

Levy D, Ronemus M, Yamrom B, Lee Y, Leotta A, Kendall J . Rare de novo and transmitted copy-number variation in autistic spectrum disorders. Neuron. 2011; 70(5):886-97. DOI: 10.1016/j.neuron.2011.05.015. View

18.

Merikangas A, Segurado R, Heron E, Anney R, Paterson A, Cook E . The phenotypic manifestations of rare genic CNVs in autism spectrum disorder. Mol Psychiatry. 2014; 20(11):1366-72. PMC: 4759095. DOI: 10.1038/mp.2014.150. View

19.

Miller D, Adam M, Aradhya S, Biesecker L, Brothman A, Carter N . Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010; 86(5):749-64. PMC: 2869000. DOI: 10.1016/j.ajhg.2010.04.006. View

20.

Richards C, Jones C, Groves L, Moss J, Oliver C . Prevalence of autism spectrum disorder phenomenology in genetic disorders: a systematic review and meta-analysis. Lancet Psychiatry. 2015; 2(10):909-16. DOI: 10.1016/S2215-0366(15)00376-4. View