In this study, we generated a comprehensive description of the ASD profile in children with de novo disruptive GRIN2B variants to elucidate unique features relative to other LGD and ASD comparison groups. Our findings indicate a distinct GRIN2B ASD phenotype that displayed fewer problematic social behaviors and impairing RRBs. Specifically, we note intact socioemotional reciprocity and fewer reported challenges with the rigidity of routines or restricted interests, which were supported and contextualized by clinical observations. Here, we discuss the constellation of features in more depth and describe implications for clinical outcomes and treatment.
Strengths in socioemotional reciprocity.
Among children with de novo GRIN2B variants, socioemotional reciprocity appears to be a unique strength of the phenotype relative to LGD and idiopathic ASD groups. Social smiling and shared enjoyment with others were also reported in over half the GRIN2B group. Historical lifetime prevalence of reciprocal friendships also confirms an intact social motivation profile. Roughly half of the GRIN2B sample demonstrated frequent social overtures towards examiners or caregivers as indicated by ADOS-2 item scores. Additionally, parent report on the SRS-2 indicated that GRIN2B participants exhibited less social motivation difficulties compared to the idiopathic ASD group. This is in contrast to SRS-2 profiles among several known ASD-associated mutation groups; for example, individuals with CHD8 and FMR1 mutations are characterized by notably low social motivation [42,43]. However, items within the social motivation SRS-2 subscale are relatively diverse, including approach/avoidance of social situations (e.g., “Would rather be alone than with others”), aspects of self-confidence, and symptoms of social anxiety (e.g., seems much more fidgety in social situations than when alone). Given previously identified associations between SRS scores and genetic risk [44], it may be helpful to engage in a more fine-grained item-level analyses to better specify areas of social strengths in GRIN2B children that can be captured by parental report.
Extending from clinical observations noted within the case reports and clinical descriptions, GRIN2B participants were frequently characterized as demonstrating high social motivation and approach, consistent with quantitative data across both gold-standard clinical assessments and parent-report. Overall, the social exuberance observed in the current sample is consistent with previous characterizations describing individuals with de novoGRIN2B mutations as “trusting” and “socially boundless”[15]. Interestingly, qualitative notes stratified by ASD diagnosis revealed similar profiles of social motivation and approach, such that regardless of whether the child met strict ASD diagnostic criteria, socioemotional reciprocity was noted as a strength. Continued phenotyping work is encouraged to delineate and identify how social strengths may be unique in GRIN2B populations and can be leveraged to bolster social skills and communication interventions.
Inappropriate social responses.
Despite social strengths in motivation and approach, GRIN2B social profiles also demonstrate consistently inappropriate or limited social response. ADI-R items indicated elevated problems as a young child with appropriateness of social responses (item 59) compared to the pathogenic and ASD Low NVIQ groups. Within qualitative data examined, social response was commonly described as limited, including clinical descriptions such as “socially naïve, unsure what to say and do”, “does not respond to attempts by others to engage”, and “inappropriate facial expressions (hysterical laughter)”. Participants with verbal skills also demonstrated noted difficulty sustaining reciprocal conversation. Clinical characterizations of this difficulty included a limited ability to sustain conversation outside of the participant’s own interests and requiring repeated probes to report on events.
As impairments in social interactions are a key diagnostic feature of ASD, it is critical to characterize differences across social motivation and social response among etiologically distinct subgroups to inform precision medicine. One theory is that early alterations to social motivation and reward appear to alter underlying mechanisms that ultimately disrupt social processing in ASD [45], supported by work in neuroimaging [46–48]. It may be possible that social motivation serves as a protective factor for children with de novo GRIN2B mutations, whereas inappropriate social responses may reflect underlying social misjudgment [49]. Prior work in a large ASD sample indicated that despite evidence that high social motivation can facilitate social skills, social dysregulation (e.g., internalization, aggressive behaviors, irritability) may interfere with positive outcomes [50]. Because social response appears to be a limitation to the GRIN2B social profile, social skills interventions could target these specific challenges (e.g., reciprocal conversation skills and appropriate response to the approach of others). Additionally, given current efforts to determine how pharmacological intervention may be able to rescue social function in animal models [51], continuing to fine-tune what social functions should be targeted in GRIN2B (and other genetic etiologies of ASD) will be critical.
Perhaps related to these inappropriate social responses, children with de novoGRIN2B variants were much more likely to receive an ASD diagnosis than population estimates of ~1.6% [52]. In our sample, 8/13 (62%) of those receiving an in-person research assessment received an ASD diagnosis by a licensed clinical psychologist using DSM-5 criteria [26]. The intact social interest and social disinhibition widely observed in GRIN2B is similar to the “active-but-odd” social interaction subtype originally proposed by Wing and Gould in 1979 [53]. This style of interaction is characterized by active seeking of contact and interactions, although social initiations and responses are generally unusual and/or inappropriate (i.e., personal space boundary violations, asking personal questions, talking at length about a circumscribed or unusual interest). The active-but-odd interaction style in ASD has been associated with higher cognitive ability and adaptive skills, decreased autism severity, motor deficits, and attention deficit and hyperactivity symptoms [54–56]. Our results further expand previous characterizations of GRIN2B social interactions, such that approach appears intact but response is limited, which may potentially be linked to specific molecular mechanisms [11,14,15].
Disentangling the role of cognition in ASD symptomology.
All GRIN2B participants who completed cognitive and adaptive testing met criteria for ID or GDD, providing additional evidence for the connection between ID and disruptive mutations to this gene [8,11,14,15,57]. Diagnosis of ASD in the context of ID is challenging, particularly among individuals with severe to profound ID or co-occurring motor, vision, or hearing impairments [58]. Standardized assessments of ASD symptoms (e.g., the ADOS-2, ADI-R, and SRS-2) have reduced specificity and validity for individuals with severe cognitive, motor, or sensory impairment, so clinical judgment is needed when using these instruments to inform diagnosis [58–60]. Social communication deficits as compared to same-age peers are characteristic of ID; as such, it may be difficult to determine whether observed social communication deficits are inconsistent with developmental level as opposed to chronological age [26,60,61].
Additionally, there is considerable overlap in the restricted and repetitive behaviors observed in individuals with ASD and comorbid ID and individuals with ID only. Specifically, similar rates of repetitive actions on objects, need for sameness, repetitive motor mannerisms, preoccupation with parts of objects, and nonfunctional routines and rituals have been found in both populations [62–66]. DSM-5 criteria that appear to best distinguish between ASD with ID and ID only include poor nonverbal communication (e.g., coordinated eye contact), reduced showing and sharing of interests, limited social emotional reciprocity, and the presence of restricted interests being related to ASD [63,64]. Differentiating the role of cognitive impairment in the presentation of ASD symptoms in individuals with GRIN2B is complicated by the many overlapping clinical features in both neurodevelopmental conditions.
Overall, individuals with ID-associated genetic disorders often present with a complex and idiosyncratic profile of cognitive, language, motor, medical, psychiatric, and behavioral impairments, which may contribute to over diagnosis or inconsistent diagnosis of ASD in genetic disorders [58,67–69]. Future research on ASD profiles in GRIN2B and other rare ASD-associated genetic disorders should continue to incorporate novel measures that are aligned with developmental level and validated for individuals with severe to profound ID [58–61,70].
Limitations of the current study:
The findings of this study should be considered in the context of study limitations. First, while this study provides an in-depth look at the ASD profile of the largest GRIN2B cohort to date, the sample size, particularly those with clinically-assessed ASD severity, remains small, which limited quantitative analyses and the extent to which findings can be applied broadly to the GRIN2B population. Within the current study, GRIN2B cases were identified from two different sources, each of which differed in the amount of clinical phenotyping that was conducted and availability of complete data across cases. Due to the small sample size, we adopted the traditional (albeit potentially problematic [71]) statistical significance threshold of p < 0.05 that may have contributed spurious findings. Given that the goal of this study was to provide an initial characterization of the comprehensive GRIN2B ASD profile and was not assessing efficacy of a clinical trial, we argue that this threshold was sufficient for our purposes. However, continued phenotyping efforts are needed to increase size of future cohorts with particular attention paid to harmonizing quantitative assessment tools for consistent characterization of patients.
A limitation of comparisons between GRIN2B, Pathogenic, and ASD comparison groups should also be noted. While GRIN2B and Pathogenic groups were matched on sex, age, and cognitive ability, an age-matched “idiopathic” ASD comparison group was not available for analyses. The ASD comparison group was significantly older than the GRIN2B and Pathogenic groups, which may impact symptom presentation comparisons across groups. Future studies would benefit from an age-matched comparison group to further understand differences in GRIN2B and idiopathic ASD profiles.
The current study focused on clarifying and informing socioemotional and RRB profiles for GRIN2B. However, as with many high-confidence neurodevelopmental disorder risk genes, GRIN2B is also characterized by significant medical and psychiatric comorbidities, which were not the focus of this study. Medical conditions including hypotonia, gastrointestinal disturbances, sleep difficulties, and seizures have been noted in GRIN2B at rates consistent with other neurodevelopmental disorder risk genes. Additionally, attention difficulties and hyperactivity are frequently reported in those with GRIN2B variants. These medical and psychiatric comorbidities are likely to impact development and behavioral presentation and should be considered in future analyses to clarify the communication, social, and behavioral profiles of patients with GRIN2B mutations.
Lastly, the current study did not evaluate phenotypic presentation of GRIN2B variants in tandem with a functional characterization of the genetic variants. Recent publications report a range of functional consequences of disruptive mutations in GRIN2B and suggest a possible link between gain of function mutations and epilepsy, although significantly more research is needed in this area [8,11]. Additional multidisciplinary collaborations that connect functional mechanisms of GRIN2B to clinical presentation is essential to understanding the role of GRIN2B in NDD risk and identifying points of pharmacological and behavioral intervention.