Table 4.

Summary of top genes

	NRXN1	REEP3	CTTNBP2	HTR2A
Gene product/brain relevance	Synaptic cell-adhesion protein/synapse functioning and development in the cortical-striatal pathway40, 41	Microtubule-binding protein/possible role in synaptic plasticity, calcium signaling, shaping tubular ER membranes in neurons46	Cortical actin (cortactin)-binding protein/synaptic maintenance48	G-protein-coupled serotonin receptor/cortical neuron excitation63
Disease relevance	Neurodevelopmental disorders incl. ASD42, 64	ASD45	Interacts with CDH2, implicated in canine CD8, 9, 65	ASD, OCD35, canine CD (5-HT3 receptors)49
Reason for inclusion as candidatea	(1) Model (mouse) organism gene; (2) ASD gene	(2) ASD gene	(1) Model (mouse) organism gene	(1) Model (dog) organism gene; (2) human candidate—SSRI target
Type of burden identified	Coding variants—missense variants over-represented to one isoform, NRXN1a-2	Regulatory variants	Regulatory variants	Coding variants—missense variant in perfect linkage to a common variant rs6314 associated with response to SSRIs50
Validation of variants identified in present study	By comparison to ExAC—genome-wide-significant association	By EMSA—disrupt regulatory elements bound by various TF, including GATA2	By EMSA—alter epigenetic marks active in the cortico-striatal pathway	By genotyping independent cohort; too few polymorphic sites for validation with ExAC
Hypothesized impact of variants identified	Inaccurate cellular localization of NRXN1, or altered binding competition to its partner, modifying synaptic adhesion43	REEP3 expression in GABA neurons inhibited by variants that reduce GATA2 binding47, leading to excitatory/inhibitory imbalance in CSTC circuit30	Altered CTTNBP2 expression in cortical-striatal circuit in brain66	Altered binding affinity of HTR2A, changing the activation of downstream calcium signaling in neurons32

^aFor explanation of each category, see “Results” section