Table 1 Summary of evidence for candidate ASD-related endophenotypic trait domains (ETDs) across multiple levels of analysis. ETDs described here represent some of the most promising targets for ASD research on endophenotypes based on accumulating evidence showing targeted phenotypes are quantitative, translational, present in unaffected relatives of autistic individuals, and measurable across multiple units of analysis. This table is not intended to be a comprehensive list of candidate ETDs associated with ASD but represents perhaps the most promising ETDs based on existing data

Neuropsychological and Behavioral

Relative to age-matched neurotypical controls, autistic children show reduced attention to eye regions of faces [101, 102]; Autistic adolescents and adults show reduced attention to faces [103, 104]

Infants later diagnosed with ASD show declining rates of gaze shifts towards the eye regions of others between 2–6 months resulting in reduced overall attention to faces relative to neurotypical peers [102]

Parents and siblings of autistic individuals show atypical social gaze [51, 105], and parents with broader autism phenotypic (BAP⁺) characteristics show decreased gaze towards social stimuli in complex scenes relative to population controls and parents of autistic individuals who do not show BAP features (BAP-; [105, 106])

Autistic individuals show higher mean pitch, greater pitch variability, and longer voice duration in autistic individuals relative to controls [107, 108]

Pain cries from 6-month-olds with a family history (FH) of autism are higher and more variable in pitch than infants with no FH (nFH) [46]

Cries of 15-month-old FH toddlers show higher frequencies [42] and are shorter in duration than nFH toddlers [42, 109]

FH infants later diagnosed with autism (FH⁺) have higher fundamental frequencies than FH infants who do not develop autism (FH⁻); FH- infants have higher fundamental frequencies than infants without FH of autism, (FH +  > FH- > nFH) [42]

Parents of autistic children show some overlap with their offspring in suprasegmental speech, including greater variability in frequency, especially for mothers showing high levels of BAP features [108]

Across large age ranges, autistic individuals show increased rates of errors during tests of behavioral response inhibition (e.g., stop signal task, antisaccades) associated with more severe clinically rated RRBs [67, 110,111,112]

Compared to respective controls, autistic individuals and their first-degree relatives show a reduced ability to shift behavioral responses during neuropsychological tests of cognitive flexibility (e.g., probabilistic reversal learning, set shifting) [113,114,115]

Autistic individuals and their parents show increased rates of errors on probabilistic learning and stop signal tasks; reversal learning errors were more severe in BAP + parents and their children relative to BAP- families; cognitive flexibility and inhibitory control error rates were increased in autistic children of BAP+ parents and associated with more severe ASD symptomatology [67]

Autistic individuals show increased force variability in precision grip manual motor output relative to neurotypical controls during a steady state force maintenance task [116]

Infants with different ASD-risk status show stepwise patterns in quantitative measures of reach-to-grasp movements such that FH + infant siblings had worse scores on the Skilled Reaching Rating Scale than FH- and nFH infants [117]

Infants with different ASD-risk status show stepwise patterns in behaviorally coded postural control behaviors (e.g., lying, supported or unsupported sitting, resting on all four limbs, supported and unsupported standing) indicating delayed trajectories of primary postural positions in FH + infants, relative to FH- with language delay, FH- without language delay and nFH [FH +  < FH- with language delay < FH- without language delay = controls; [118]

Parents and siblings of autistic individuals show reduced accuracies of saccadic eye movements, reduced smooth pursuit eye movement velocity during closed-loop phases and lateralized reductions of smooth pursuit eye movements during the open-loop phase implicating reduced lateralization of sensorimotor behavior [119]

First-degree relatives of autistic individuals showed similar open-loop pursuit gain for rightward and leftward movements, whereas same-age controls showed greater gain for rightward relative to leftward movements implicating left hemispheric dominance [119]

Brain (cellular, circuit and network levels)

Autistic individuals consistently show prolonged N170 latencies to images of faces suggesting delayed or less automated processing of facial information [120, 121]

Autistic individuals and their unaffected siblings also demonstrate a reduced difference in N170 amplitudes between inverted and upright faces compared to controls suggesting reduced specialization of neural processing of facial information that is familial [122]

First-degree relatives of autistic individuals show diminished right lateralization of N170 while viewing static images of faces relative to respective neurotypical control groups suggesting familial patterns of altered developmental specialization of select social brain networks [123, 124]

Autistic individuals and their siblings show reduced functional activation to faces in amygdala, fusiform face area, left frontal gyrus, right middle prefrontal cortex (PFC), left posterior PFC, left dorsomedial PFC, and temporal poles relative to controls [125]

Parents of autistic individuals show increased functional activation in fusiform face area and amygdala compared to control parents; BAP+ parents have greater right fusiform gyrus activation than BAP- and control parents [126]

Autistic individuals show less stable frequency following responses (FFRs) to speech sounds relative to non-autistic peers suggesting greater levels of variability in processing auditory information [127]

Autistic individuals and their parents show reduced auditory P1 amplitudes relative to age-matched controls, reflecting less robust detection of changes in pitch during auditory feedback [128]

Autistic individuals show reduced activation in both prefrontal cortex and ventral striatum when attempting to shift to a new behavioral response after removal of reinforcement for a previously correct response [129]

Autistic individuals show atypical activation of anterior cingulate during an antisaccade task requiring participants to look away from suddenly appearing targets [130, 131]

Autistic individuals show reduced activations across frontal and parietal eye fields during antisaccades relative to non-autistic controls [132]

Autistic individuals show atypical activation of premotor and parietal cortex during manual motor behaviors relative to controls [133, 134]

Autistic individuals show reduced functional connectivity of inferior parietal lobule and cerebellum and atypical age-related differences in cerebellar-cortical functional connectivity during manual motor behavior [133]

Autistic individuals show right lateralization motor circuit connectivity during task-free functional MRI compared to controls associated with more severe clinically rated motor impairments [135]

Lesions of posterior cerebellar vermis in non-human primates impair feedback mechanisms supporting saccade accuracy [136]; persistent deficits in modulating accuracy across repeated events/trials highlight a critical role in error feedback correction that also is seen in autistic individuals implicating cerebellar modulation of brainstem circuits [137]

Molecular and genetic

Non-human primates with TALEN-edited MECP2 mutations show a preference for social over nonsocial stimuli and look to conspecific faces exhibiting aggressive and submissive expressions for shorter durations than neutral expressions [138]

Primate offspring of maternal immune activation ASD models show multiple gaze differences relative to control animals, including longer latencies to fixate on the eye region of conspecific faces, fewer fixations directed at the eyes, and less fixation time on the eyes [139]

Multiple mouse models of ASD show reduced social approach relative to wild-type (WT) mice [140, 141]; Rescue of social approach deficits with R-Baclofen in BTBR mice [142] and mice with 16p11.2 microdeletion [143] suggest reduced GABA_B function associated with reduced social attention in preclinical models of ASD

SHANK3 KO mice and other preclinical models of ASD show higher peak frequencies and reduced modulatory abilities in vocalizing relative to wild type mice [144, 145]

BTBR mice exhibit elevated rates of errors during reversal learning [146, 147]

Reversal learning deficits in BTBR mice were rescued with administration of an adenosine A_2a receptor agonist and 5HT_2a receptor antagonist in dorsomedial striatum [148, 149]

DVL1-modified and FMR1 KO mice show atypical sensorimotor gating [150, 151]

Rescue of cerebellar Purkinje cell function and atypical gait and balance phenotypes was achieved through the mTOR pathway [152, 153]

In a valproic acid exposure mouse model of ASD, mice demonstrated specific cell loss in motor cortex and cerebellum and motor impairments that were associated with Purkinje cell loss in Crus I [151]