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. Author manuscript; available in PMC: 2021 Mar 15.
Published in final edited form as: Child Health Care. 2020 Mar 17;49(4):361–384. doi: 10.1080/02739615.2020.1741361

Co-occurring medical conditions among individuals with ASD-associated disruptive mutations

Evangeline C Kurtz-Nelson 1, Jennifer S Beighley 1, Caitlin M Hudac 2, Jennifer Gerdts 1, Arianne S Wallace 1, Kendra Hoekzema 3, Evan E Eichler 3,4, Raphael A Bernier 1
PMCID: PMC7958308  NIHMSID: NIHMS1579175  PMID: 33727758

Abstract

Children with autism spectrum disorder (ASD) are at risk for co-occurring medical conditions, many of which have also been reported among individuals with mutations in ASD-associated genes. This study examined rates of co-occurring medical conditions across 301 individuals with disruptive mutations to 1 of 18 ASD-risk genes in comparison to rates of conditions in an idiopathic ASD sample. Rates of gastrointestinal problems, seizures, physical anomalies, and immune problems were generally elevated, with significant differences in rates observed between groups. Results may inform medical care of individuals with ASD-associated mutations and research into mechanisms of co-occurring medical conditions in ASD.

Introduction

Approximately one out of 59 children in the United States is diagnosed with autism spectrum disorder (ASD), a neurodevelopmental disability defined by social communication deficits and the presence of restricted or repetitive behaviors, interests, or activities (Baio et al., 2018). In addition to social, behavioral, and psychiatric challenges, children and adolescents with ASD are at increased risk for a number of co-occurring medical conditions as compared to typically developing children. In particular, elevated rates of gastrointestinal (GI) problems and seizures have been reported across prevalence and comorbidity studies, while other studies suggest increased rates of immune problems, hearing problems, and vision problems (Kielinen, Rantala, Timonen, Linna, & Moilanen, 2004; Tye, Runicles, Whitehouse, & Alvares, 2018; Xu et al., 2018). In addition, a subset of individuals with ASD present with multimorbidity, or multiple simultaneous co-occurring medical conditions (e.g., co-occurring seizures and GI problems; Aldinger, Lane, Veenstra-VanderWeele, & Levitt, 2015; Vargason, Frye, McGuinness, & Hahn, 2019). These medical comorbidities can impact overall development, increase caregiving burden and costs, reduce access to educational and social opportunities, and contribute to increased mortality in ASD (Tye et al., 2018).

While increased rates of certain co-occurring medical problems have been well established in ASD, the biological mechanisms and etiologies underlying these conditions are not well understood. ASD is characterized by significant phenotypic heterogeneity with marked variation in ASD symptoms and severity among individuals (Georgiades et al., 2013). This heterogeneity stems in part from the diverse range of genetic and environmental interactions that contribute to ASD presentation and symptoms, which creates barriers to identifying the etiology of ASD and its co-occurring medical conditions (Masi, DeMayo, Glozier, & Guastella, 2017; Tye et al., 2018). Several mechanisms have been hypothesized to contribute to both ASD symptoms and co-occurring medical conditions, including alterations in the gut-brain axis and microbiotia, dysfunction in serotonin expression and GABA transmission, and abnormal cytokine signaling (Jacob, 2016; Masi, Glozier, Dale, & Guastella, 2017; Mayer, Padua, & Tillisch, 2014; Tye et al., 2018). However, these proposed mechanisms are yet to be confirmed, and co-occurring medical conditions in ASD are likely the result of interactions between complex systems that are idiosyncratic to individuals (Neumeyer et al., 2019; Tye et al., 2018). Identifying the factors that contribute to co-occurring medical conditions in ASD may help elucidate these mechanisms and inform prevention and treatment of significantly impairing medical conditions for children and adolescents with ASD.

In the past decade, exome sequencing technologies have identified a number of disruptive mutations in single genes that directly contribute to ASD (Iossifov et al., 2012; O’Roak et al., 2012). De novo mutations in these ASD-risk genes are currently proposed to account for up to 10% of ASD cases (Krumm, O’Roak, Shendure, & Eichler, 2014; Ramaswami & Geschwind, 2018). ASD-risk genes are typically highly conserved and expressed neurologically, and high confidence ASD-risk genes include genes involved in chromatin remodeling (e.g., CHD8), sodium ion channels (e.g., SCN2A), and brain growth and development (e.g., DYRK1A; Krumm et al., 2014). Identification and confirmation of ASD-risk genes has led to a genotype-first approach in ASD research, in which individuals with disruptive mutations in high-confidence risk genes complete clinical phenotyping to inform genotype-phenotype relations (Arnett, Trinh, & Bernier, 2019; Stessman, Bernier, & Eichler, 2014). The genotype-first approach allows for the identification of genetic ASD subtypes with unique clinical profiles and enhances our understanding of how genetic mechanisms contribute to phenotypic heterogeneity in ASD (Arnett et al., 2019; Stessman et al., 2014).

This genetics first approach has identified co-occurring medical conditions that appear to be present at high rates in specific gene cohorts. For instance, individuals with disruptive CHD8 mutations exhibit increased rates of constipation as compared to children with ASD and no CHD8 mutation, indicating that mutations in this gene may impact gastrointestinal motility (Bernier et al., 2014). GI and feeding problems have been reported in several gene cohorts, including ASXL3, DYRK1A, HNRNPH2, PACS1, and STXBP1 (Bain et al., 2016; Balasubramanian et al., 2017; Earl et al., 2017; O’Brien et al., 2019; Schuurs-Hoeijmakers et al., 2016). Many ASD-risk genes are associated with increased seizure risk, but seizure type and severity vary across groups. For example, mutations in SCN2A contribute to infantile or childhood-onset seizures depending on mutation type (i.e., gain-of-function or loss-of-function), while individuals with SYNGAP1 mutations typically exhibit absence seizures and eyelid myoclonia (Sanders et al., 2018; Vlaskamp et al., 2019). Other co-occurring medical conditions have been primarily reported in specific gene groups, such as microcephaly in DYRK1A and CHAMP1, macrocephaly in CHD8 and PPP2R5D, and kidney/urinary abnormalities in ARID1B and FOXP1 (Bekheirnia et al., 2017; Bernier et al., 2014; Earl et al., 2017; Shang et al., 2016; Tanaka et al., 2016; van der Sluijs et al., 2019). Table 1 shows co-occurring conditions that have been associated with specific ASD-risk genes via recently published case series.

Table 1.

Co-occurring conditions previously associated with genetic mutation groups.

Co-Occurring Condition Genes Previously Associated
Constipation ADNPa, ARID1Bb, CHD8c
Non-Febrile Seizures DYRK1Ad, PACS1e, SCN2Af, STXBP1g, SYNGAP1h
Macrocephaly CHD8c, PPP2R5Di
Microcephaly CHAMP1j, DYRK1Ad
Recurrent Otitis Media ADNPa, FOXP1k
Cardiac Problems ADNPa, ARID1Bb, CSNK2A1l, MED13Lm, PACS1e
Genital Problems ARID1Bb, PACS1e, SETBP1n
Kidney/Urinary Problems ARID1Bb, FOXP1o
Vision Problems ADNPa, ARID1Bb, DYRK1Ad
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Taken together, case series of individuals with disruptive mutations in ASD-risk genes suggest elevated rates of co-occurring medical problems frequently reported in ASD (e.g., GI problems and seizures) as well as gene-specific medical problems not commonly observed in ASD (e.g., cardiac abnormalities). However, few studies have compared rates of co-occurring conditions across genetically-defined groups and in relation to idiopathic ASD (i.e., ASD without a known genetic cause). As such, it is unclear whether symptoms noted in case reports are occurring at higher rates than seen in ASD more broadly. Rates of co-occurring medical conditions are rarely compared across gene groups, which limits our understanding of how specific genetic factors and processes may contribute to co-occurring medical conditions in ASD. In addition, some medical problems have yet to be investigated in the subset of children with disruptive mutations to ASD-risk genes. For example, despite high rates of allergies and immune problems reported in ASD, little information is available as to the prevalence of immune problems in ASD-risk gene groups. By identifying medical conditions that are consistently associated with mutations in ASD-risk genes, we may identify mechanisms contributing to co-occurring medical problems in ASD, as well as future targets for the treatment and prevention of these conditions.

The aim of this study was to systematically examine and compare rates of co-occurring medical conditions across individuals with disruptive mutations to ASD-risk genes. To establish a large cohort of individuals with rare mutations, data were combined from two projects using a genotype-first approach to understanding genetic mechanisms in ASD: an ongoing NIMH funded study (TIGER study; Beighley et al., 2019) and the Simons Variation in Individuals Project, Phase Two (SVIP; Simons VIP Consortium, 2012). For these studies, individuals were ascertained based on the presence of a disruptive variant to recurrently identified ASD-associated genes, regardless of psychiatric or medical diagnoses. To better understand the extent to which co-morbidities are related to genetic etiologies, medical problems in this cohort were compared to children and adolescents with ASD but no known genetic etiology, as confirmed by exome sequencing (herein described as idiopathic) from the Simons Simplex Collection (SSC; Fischbach & Lord, 2010; Sanders et al., 2015), who were ascertained based on the presence of an ASD diagnosis. These three studies (TIGER, SVIP, and SSC) have similar approaches to phenotypic characterization, allowing for combination of data and direct comparison of rates across groups. We hypothesized that individuals with a mutation in a gene previously associated with a specific medical condition (as listed in Table 1) would show elevated prevalence of this co-occurring condition when compared to individuals with mutations in other known ASD-risk genes. For example, given the high rates of seizures reported in case series of individuals with mutations in SCN2A (e.g., Sanders et al., 2018), we hypothesized that individuals with mutations in SCN2A would show a significantly elevated rate of non-febrile seizures when compared to a sample of individuals with mutations in 17 other ASD-risk genes. In addition, rates of co-occurring conditions that have not been widely or systematically reported in case series were examined to provide descriptive information about prevalence across groups.

Methods

Participants

Participants in this study included 301 individuals with disruptive mutations to ASD-risk genes (ages 7 months to 38 years, mean age = 8 years, 50.5% female). Individuals in both TIGER and SVIP were recruited based on previous identification of a disruptive mutation to a high-confidence ASD-risk gene through clinical or research genetic testing. Participants were included in the current study if review of genetic findings confirmed the presence of a pathogenic or likely pathogenic mutation in a known ASD-associated gene (Nakashima et al., 2019; Feliciano et al., 2018; Stessman et al., 2017) and medical history information was available from five or more individuals with a disruptive mutation in a specific gene. Gene, variant, and inheritance information for participants are listed in the Supplemental Appendix. Seven gene groups (ADNP, DYRK1A, GRIN2B, MED13L, SCN2A, SETBP1, STXBP1) included participants from both TIGER and SVIP, eight groups (ASXL3, CHAMP1, CSNK2A1, HIVEP2, HNRNPH2, PACS1, PPP2R5D, SYNGAP1) included participants from SVIP only, and three groups (ARID1B, CHD8, FOXP1) included participants from TIGER only. In total, 32 individuals (10.6%) participated in TIGER and SVIP as confirmed by matching genetic and phenotypic information, 195 (64.8%) participated in SVIP only, and 74 individuals (24.6%) participated in TIGER only. Groups did not significantly differ across study (TIGER, SVIP, or both) in adaptive behavior skills (as measured by the Vineland-II Adaptive Behavior Composite (Sparrow, Balla, and Cicchetti, 2005; F(2, 289) = 0.71, p = .50), ASD symptom severity (as measured by the total T-score of the Social Responsiveness Scale, Second Edition (Constantino & Gruber, 2012; F(2, 177) = 0.84, p = .43), and sex (F(2, 298) = 1.24, p = .29). However, study participants in the TIGER group were significantly older than those in the SVIP group, F(2, 298) = 4.68, p = .01. Cognitive assessment scores were not available for SVIP-only participants, so cognitive skills could not be compared across studies.

To create a comparison group, rates of co-occurring medical problems were examined in 2,676 individuals with idiopathic ASD from SSC (ages 4 years to 18 years, mean age = 9 years, 13% female). SSC represents a large and well-characterized cohort of 2,761 children meeting strict diagnostic criteria for ASD and adolescents whose parents and siblings do not have ASD or ASD traits (Fischbach & Lord, 2010). SSC participants completed whole exome sequencing, and 85 SSC participants with a likely gene disrupting mutation in any of 65 ASD-risk genes as identified by Sanders and colleagues (2015) were removed from analyses. As such, the 2,676 participants included in the idiopathic comparison do not have a likely pathogenic mutation in any of these 65 known ASD-risk genes.

Each study (TIGER, SVIP, and SSC) was approved by the local institutional review board. Informed consent was obtained from all participating caregivers, and informed consent or assent was obtained from probands who were capable of providing consent or assent. Data collection for TIGER is ongoing, and data were accessed locally. De-identified data from SVIP and SSC were accessed and released via the Simons Foundation Autism Research Initiative following specified data-access procedures, which included both foundation and institutional review board approval.

Measures

Structured and comprehensive medical and psychiatric history interviews with primary caregivers were completed for all participants (TIGER, SVIP, and SSC). The medical history interviews used by TIGER and SVIP were adapted from the SSC medical history interview. Interviews assessed history of both specific medical problems (e.g., constipation or febrile seizures) and broader categories of co-occurring conditions (e.g., vision problems or cardiac problems). Broader categories captured varied medical conditions, including structural or congenital problems (e.g., congenital malformations) as well as acquired problems (e.g., nearsightedness or asthma). For participants who completed both TIGER and SVIP, the most recently administered medical history interview was included in analyses. Participants in TIGER and SSC completed an additional battery of clinical and diagnostic assessments, and diagnoses of ASD and intellectual disability (ID) were confirmed or newly provided by expert clinicians using the Diagnostic and Statistical Manual of Mental Disorders, 4th or 5th Edition (American Psychiatric Association, 2000, 2013). In addition, occipital frontal head circumference measurements were completed for a subset of TIGER participants (n = 71) and SSC participants (n = 2,540), and age- and sex-standardized z-scores were calculated based on population norms (Roche, Mukherjee, Guo, & Moore, 1987). For these participants, macrocephaly was coded as present if the head circumference z-score was 2 or higher or if a previous diagnosis of macrocephaly was reported; microcephaly was coded as present if the head circumference z-score was −2 or lower or if a previous diagnosis of microcephaly was reported. Participation in SVIP Phase Two occurs remotely (online and by telephone), and head circumference measurements or clinician-confirmed diagnoses are not available for SVIP-only participants. For these participants, ASD, ID, macrocephaly, and microcephaly were coded as present if a previous diagnosis was reported by the caregiver. Information is not available as to whether or not SVIP-only participants have been previously evaluated for ASD or ID. Diagnoses of ASD and ID were not reported for CHAMP1; these data were not released from SVIP as fewer than five caregivers in the CHAMP1 group provided information on psychiatric diagnoses. All other co-occurring conditions were coded as present or absent based on caregiver report of a past or current diagnosis during the medical history interview. Recurrent otitis media was defined as eight or more lifetime occurrences of otitis media; rates of myringotomy tube placement were also examined as an indicator of otitis media severity. Major surgical history was coded as present if the participant had received any major surgery (e.g., surgery to correct a heart defect or strabismus; dental procedures would generally not be considered major surgery) during their lifetime. Allergies were coded as present if the participant was diagnosed with or suspected of having any food, environmental, or medication allergies.

Analyses

All analyses were completed in SPSS version 23 (IBM Corp., 2015). Given the presence of low expected counts across cells, Fisher’s exact test with two-sided Monte Carlo significance estimates (samples = 10,000, starting seed = 2,000,000) was used to determine whether rates of co-occurring conditions differed significantly across gene groups. Fisher’s exact test (without Monte Carlo estimates) was also used to complete planned comparisons; the frequency of a co-occurring condition in each gene group listed in Table 1 (e.g., constipation in ADNP or vision problems in DYRK1A) was compared to the frequency of that condition across all other participants with disruptive mutations. For these comparisons, Bonferroni correction was applied to the significance level (alpha) to account for the number of comparisons per co-occurring condition. For example, a corrected significance level of .017 (.05 / 3) was used to determine significance for the three separate analyses comparing constipation in ADNP, ARID1B, and CHD8 to the remainder of the sample. The SSC idiopathic comparison group was not included in analyses due to major discrepancies in sample size and phenotypic characteristics (e.g., gender); instead, rates of co-occurring conditions in the idiopathic group are presented descriptively in Figures 2–7 to allow for visual comparison.

Figure 2.

Figure 2.

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Percentage and number of participants with reported gastrointestinal problems across idiopathic ASD, all participants with an ASD-associated mutation (monogenic), and specific genetic mutation groups.

Figure 7.

Figure 7.

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Percentage and number of participants with reported immune problems across idiopathic ASD, all participants with an ASD-associated mutation (monogenic), and specific genetic mutation groups.

Results

Co-Occurring Conditions across Groups

Figure 1 displays rates of ASD and ID (clinician confirmed or parent reported) across gene groups. Note that the idiopathic group is not presented in Figure 1; the SSC sample was specifically ascertained for ASD, and clinical diagnoses of ID were not available in the released SSC data. Rates of reported ASD (p < .001) and reported ID (p < .001) differed significantly across genetic groups. However, some participants may not have been previously evaluated for ASD and ID, or they may be too young to have received a diagnosis of ASD or ID; as such, these rates likely do not reflect the true prevalence of ASD or ID in these groups. Figures 2–7 display rates of co-occurring medical conditions across gene groups, with rates in the idiopathic group and across all 301 participants with an ASD-associated mutation (hereafter referred to as the “monogenic” group) provided for visual comparison. Rates of the following co-occurring conditions differed significantly across gene groups: constipation (p = .02), gastroesophageal reflux disorder (GERD; p = .01), febrile seizures (p < .001), non-febrile seizures (p < .001), macrocephaly (p < .001), microcephaly (p < .001), cardiac problems (p < .001), genital problems (p < .001), hearing problems (p = .01), vision problems (p < .001), recurrent ear infections (p = .002), myringotomy tube placement (p < .001), and allergies (p = .03). Rates of major surgical history (p = .34), diarrhea (p = .59), kidney/urinary problems (p = .28), and respiratory problems (p = .70) did not significantly differ across groups. In general, rates of major surgical history appear to be high across genetic groups, while diarrhea, kidney/urinary problems, and respiratory problems were not commonly reported. As rates of kidney/urinary problems did not differ significantly across groups, planned comparisons for kidney/urinary problems were not completed.

Figure 1.

Figure 1.

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Percentage and number of participants with reported ASD and ID across genetic mutation groups. Participants may or may not have been previously evaluated for ASD or ID.

Constipation

Planned comparisons for constipation were conducted using a corrected significance level of p = .017. Constipation did not occur more frequently in ADNP (p = .19), ARID1B (p > .99), or CHD8 (p = .29) when compared to all other genetic mutation groups.

Non-Febrile Seizures

Planned comparisons for non-febrile seizures were conducted using a corrected significance level of .01. Non-febrile seizures were more common in SCN2A (p < .001) and STXBP1 (p = .002) as compared to all other gene groups. They did not occur more frequently in PACS1 (p > .99); significance for DYRK1A (p = .01) and SYNGAP1 (p = .01) did not survive correction.

Macrocephaly

Planned comparisons for macrocephaly were conducted using a corrected significance level of .025. Macrocephaly was more prevalent in PPP2R5D as compared to all other groups (p < .001); significance for CHD8 did not survive correction (p = .04).

Microcephaly

Planned comparisons for microcephaly were conducted using a corrected significance level of .025. Microcephaly was more prevalent in DYRK1A as compared to all other groups (p < .001); it did not occur more frequently in CHAMP1 (p = .19).

Cardiac Problems

Planned comparisons for cardiac problems were conducted using a corrected significance level of .01. Cardiac problems were more prevalent in ADNP (p < .001) and PACS1 (p < .001) than in all other gene groups. They were not more prevalent in ARID1B (p = .13), CSNK2A1 (p = .60), or MED13L (p = .65).

Genital Problems

Planned comparisons for genital problems were conducted using a corrected significance level of p = .017. Genital problems occurred more frequently in PACS1 (p = .01) and SETBP1 (p = .003) when compared to all other gene groups; they did not occur more frequently in ARID1B (p = .12).

Vision Problems

Planned comparisons for vision problems were conducted using a corrected significance level of p = .017. Vision problems were more prevalent in ADNP (p = .01), ARID1B (p = .02), and DYRK1A (p = .002) as compared to all other groups.

Otitis Media

Planned comparisons for recurrent otitis media were conducted using a corrected significance level of .025. Recurrent ear infections were more common in ADNP (p = .02) but not in FOXP1 (p > .99) when compared to all other groups.

Discussion

Rates of co-occurring medical conditions were examined across individuals with ASD-associated mutations in 18 different genes. Taken together, these individuals exhibited high rates of medical problems that warrant ongoing monitoring and treatment, including gastrointestinal problems, seizures, physical and structural abnormalities, and immune problems (allergies and recurrent otitis media). In some cases, co-occurring medical conditions were reported frequently across groups, which may reveal general effects of mutations in genes that are key to early brain development. However, notable differences in symptom presentation were observed across groups. Rates of most co-occurring medical conditions varied significantly across mutation groups, with specific gene groups exhibiting certain problems at higher rates than individuals with other ASD-associated mutations or idiopathic ASD. While most elevations in specific gene groups were consistent with published case reports, other groups did not have significantly higher rates of previously reported co-occurring conditions when compared to a sample of other individuals with disruptive genetic variants. In addition, new associations between ASD-risk mutations and co-occurring medical problems emerged through descriptive analyses.

Gastrointestinal Problems

Many gene groups in this study exhibited elevated rates of constipation, which is consistent with published literature on idiopathic ASD (McElhanon, McCracken, Karpen, & Sharp, 2014); however, several gene groups reported particularly high rates of constipation (e.g., 76.9% in DYRK1A, 66.7% in CHD8 and CSNK2A1). In contrast, diarrhea was not frequently endorsed. Constipation in this population may be the result of medical factors associated with severe developmental disabilities, including reduced activity and mobility, low fiber intake, or low muscle tone (Sullivan, 2008; Tse et al., 2000). Alternately, some disruptive mutations may contribute directly to reduced gastrointestinal motility due to their impact on neuronal development, as is proposed in CHD8 (Bernier et al., 2014). High rates of GERD were additionally observed across many gene groups, which could also reflect motility problems (Hoffman, De Greef, Haesendonck, & Tack, 2010). Functional GI studies in both human and animal models are needed to understand whether mutations in ASD-risk genes have a direct association with reduced motility, constipation, and reflux.

Seizures

While cases of non-febrile seizures were reported across nearly all gene groups, seizures were particularly characteristic in SCN2A and STXBP1, two genes that are strongly associated with early onset seizures and epileptic encephalopathy (Sanders et al., 2018; Stamberger et al., 2016). Non-febrile seizures were also reported for a majority of individuals with mutations in DYRK1A and SYNGAP1. Notably, descriptive analyses identified a potential association between DYRK1A and febrile seizures, which differs from other mutations in ASD-risk genes and is consistent with a recent mouse model of DYRK1A (Raveau, Shimohata, Amano, Miyamoto, & Yamakawa, 2018).

Structural Abnormalities

Reflecting the presence of dysmorphic features and congenital anomalies, several gene groups were uniquely characterized by physical and structural abnormalities. Macrocephaly was most strongly associated with PPP2R5D, which is consistent with the hypothesis that mutations in this gene contribute to overgrowth (Shang et al., 2016). DYRK1A was strongly associated with microcephaly, which reflects this gene’s role in neurogenesis and brain growth (Evers et al., 2017). Elevated rates of cardiac problems in ADNP and PACS1, genital problems in PACS1 and SETBP1, and vision problems in ADNP, ARID1B, and DYRK1A highlight the impact of ASD-risk genes on multiple organ systems and overall development. Exploratory analyses also indicated other gene groups that may be at risk for additional co-occurring conditions. For example, cardiac problems were reported for 42.3% of individuals with mutations in DYRK1A, and vision problems were reported for 87.5% of individuals with MED13L mutations; these rates are higher than reported in published literature reviews (Luco et al., 2016; Tørring et al., 2019). Finally, major surgical history appeared to be elevated across groups, which could reflect the presence of structural abnormalities or other medical concerns requiring intensive medical treatment.

Immune Problems

Descriptive statistics suggested that individuals with disruptive mutations to ASD-risk genes may also be at risk for immune-related problems. While rates of allergies were generally similar to idiopathic ASD, certain groups appeared to show elevated prevalence—for example, 100% of individuals with disruptive mutations to ARID1B reported food, environmental, or medication allergies. Food allergies and allergic rhinitis may be more common among children with ASD as compared to typically developing children, which may reflect immunologic dysfunction (e.g., abnormal cytokine expression) that could also be present among individuals with ASD-associated mutations (Lyall, Van de Water, Ashwood, & Hertz-Picciotto, 2015; Miyazaki et al., 2015; Tye et al., 2018; Xu et al., 2018). Recurrent otitis media was also common in some groups. Among individuals with mutations to MED13L, 75.0% reported eight or more lifetime occurrences of otitis media, and 87.5% had received myringotomy tubes. Congenital anomalies and hypotonia contribute to eustachian tube dysfunction and recurrent otitis media in other developmental disorders such as Down syndrome and Fragile X syndrome, and this may also apply to individuals with MED13L and other ASD-associated mutations (Zeisel & Roberts, 2003; Hagerman, Altshul-Stark, & McBogg, 1987). However, the results of heritability and genome-wide association studies indicate that genetic factors (e.g., variants in candidate genes) significantly contribute to recurrent otitis media and allergies in typically developing individuals (Allen et al., 2013; Bønnelykke, Sparks, Waage, & Milner, 2015; Daly et al., 2004; Rye, Blackwell, & Jamieson, 2012; Steinke, Rich, & Borish, 2008). Given genetic influence in both otitis media and allergies as well as associations between these conditions and idiopathic ASD (Adams et al., 2016; Xu et al., 2018), future research should examine whether immune deficiencies may be associated with specific ASD-risk genes.

Limitations

This study has several key limitations that should be considered when interpreting results. The presence or absence of co-occurring conditions was in most instances coded based on caregiver report, which may or may not accurately reflect the true presence of medical conditions. Caregivers may also be able to report on some conditions more accurately than others; for example, parents may be aware that their child has a cardiac condition if it requires specialized medication or treatment, but they may not be aware that their child meets criteria for macrocephaly. A subset of participants in this study were very young (2.6% of participants were under age 18 months) and may not yet have manifested or been evaluated for certain medical or psychiatric conditions. Broad categories were used to capture co-occurring conditions, so severity or exact diagnosis cannot be determined; for example, both strabismus and nearsightedness may have been captured as vision problems. Comprehensive and in-person medical phenotyping of individuals across the lifespan (e.g., adolescents and adults) is needed to determine the true prevalence and nature of co-occurring medical conditions in specific gene groups, as well as the presence and impact of multimorbidity among individuals with disruptive ASD-associated mutations. In addition, while TIGER, SVIP, and SSC used a similar medical history interview to gather information, differences in recruitment and interviewing across studies may have influenced the results presented here. Individuals in TIGER and SVIP were ascertained based on the presence of a disruptive variant and may or may not meet full diagnostic criteria for ASD, so it is important to caution against over-interpretation from descriptive comparisons to the SSC cohort given the latter’s ascertainment based on strict ASD diagnosis. Small sample sizes across gene groups are also of concern; while the genetic mutations presented here are rare, additional individuals with these mutations will strengthen associations. Overall, the results presented here should be interpreted as estimates of prevalence that require further confirmation.

Implications for Practice

Children with disruptive mutations in ASD-associated genes frequently presented with multiple co-occurring medical conditions, including GI problems, seizures, and congenital anomalies. As such, these individuals will benefit from individualized, comprehensive, and collaborative medical care. The following recommendations are given for medical providers working with this population:

  1. Exome sequencing is used to identify ASD-associated single-gene mutations and is currently recommended as a first-line genetic test for individuals with ASD or ID (Srivastava et al., 2019). It is strongly recommended that children who present with ASD and ID plus co-occurring medical conditions, facial dysmorphology, or growth differences (e.g., micro- or macrocephaly), suggesting a possible syndromic condition or genetic mutation are referred for exome sequencing.

  2. Primary care providers (PCPs) should provide a patient-centered medical home for children with ASD-associated genetic mutations. In the medical home model, PCPs collaborate with families, specialty providers, and educational systems to coordinate a plan of care for children with special health care needs (American Academy of Pediatrics, 2002). PCPs will likely need to collaborate with a number of providers, including specialists in genetic medicine, developmental disabilities, gastrointestinal problems, epilepsy, and other areas (Shahidullah, Azad, Mezher, McClain, & McIntyre, 2018). For children with complex medical needs, the medical home may also be provided through comprehensive care programs or tertiary care-primary care partnerships (Casey et al., 2011; Gordon et al., 2007).

  3. Children with mutations in ASD-risk genes should be assessed and monitored for co-occurring conditions associated with their specific gene group. For example, individuals with mutations in ADNP or PACS1 should be screened and monitored for cardiac problems.

  4. Constipation is a common co-occurring condition among individuals with ASD-associated mutations, which can have severe consequences if not properly treated (Sparks, Cooper, Hayes, & Williams, 2018). PCPs working with children who have ASD-associated mutations should screen for constipation and treat or refer to specialists as appropriate.

  5. While non-febrile seizures are strongly associated with mutations in certain ASD risk genes, cases of seizures were reported in 17 out of 18 ASD-associated gene groups. As such, individuals with ASD-associated mutations should also be screened for history of seizures. Providers may benefit from collaboration with specialists in epilepsy genetics and clinicians with expertise in the differential diagnosis of seizures in ASD and ID (Kerr et al., 2009; Myers, Johnstone, & Dyment, 2019).

  6. Families of children with mutations in ASD-risk genes should be encouraged to participate in family groups (e.g., foundations and social media groups) for individuals with similar genetic changes. These groups allow family members to discuss common challenges and share information about the identification and treatment of co-occurring medical conditions, and they also offer a platform for effective collaboration between researchers, clinicians, and families (Schuurs-Hoeijmakers et al., 2016).

As ASD-risk genes are identified and validated, phenotyping of individuals with disruptive mutations in these genes has identified potential genetic contributors to co-occurring medical conditions across the autism spectrum. Future research should confirm these mechanisms through animal models of single-gene mutations and comprehensive medical and longitudinal studies of individuals with these mutations. Variability within gene groups should also be considered, as individuals with mutations in the same ASD-associated gene present with different medical profiles; additional research should explore the genetic and environment factors that contribute to within-group variation. In the future, targeted and personalized treatments for co-occurring medical conditions associated with specific mutations could be developed and evaluated using a personalized healthcare approach (Higdon et al., 2015). Finally, information about co-occurring conditions associated with ASD-risk genes should be disseminated to medical providers and used to inform early identification and effective medical intervention for this population.

Supplementary Material

Supplementay Material

Figure 3.

Figure 3.

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Percentage and number of participants with reported seizures across idiopathic ASD, all participants with an ASD-associated mutation (monogenic), and specific genetic mutation groups.

Figure 4.

Figure 4.

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Percentage and number of participants with reported macrocephaly and microcephaly across idiopathic ASD, all participants with an ASD-associated mutation (monogenic), and specific genetic mutation groups.

Figure 5.

Figure 5.

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Percentage and number of participants with reported structural problems across idiopathic ASD, all participants with an ASD-associated mutation (monogenic), and specific genetic mutation groups.

Figure 6.

Figure 6.

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Percentage and number of participants with reported hearing and vision problems across idiopathic ASD, all participants with an ASD-associated mutation (monogenic), and specific genetic mutation groups.

Acknowledgements

We thank the children and families for their participation in this study. We are grateful to all of the families at the participating Simons Simplex Collection (SSC) sites, as well as the principal investigators (A. Beaudet, R. Bernier, J. Constantino, E. Cook, E. Fombonne, D. Geschwind, R. Goin-Kochel, E. Hanson, D. Grice, A. Klin, D. Ledbetter, C. Lord, C. Martin, D. Martin, R. Maxim, J. Miles, O. Ousley, K. Pelphrey, B. Peterson, J. Piggot, C. Saulnier, M. State, W. Stone, J. Sutcliffe, C. Walsh, Z. Warren, E. Wijsman). This work was supported by the National Institutes of Mental Health [MH100047 to RAB; MH101221 to EEE] and by a grant from the Simons Foundation (SFARI#198677 to RAB).

Footnotes

Declaration of Interest

E.E.E. is on the Scientific Advisory Board of DNAnexus, Inc. The remaining authors have no conflicts of interest to report.

Data Availability Statement

The data that support the findings of this study are available on request from the National Database for Autism Research (RRID: SCR_004434) and the Simons Foundation Autism Research Initiative (RRID: SCR_004261).

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