Family history of psychiatric conditions and development of siblings of children with autism

Abstract

Younger siblings (SIBS) of children with autism exhibit a wide range of clinical and subclinical symptoms including social, cognitive, language, and adaptive functioning delays. Identifying factors linked with this phenotypic heterogeneity is essential for improving understanding of the underlying biology of the heterogenous phenotypic outcomes and for early identification of the most vulnerable SIBS.

Prevalence of neurodevelopmental (NDD) and neuropsychiatric disorders (NPD) is significantly elevated in families of children with autism. It remains unknown, however, if the family history associates with the developmental outcomes among the SIBS.

We quantified history of the NDDs and NPDs commonly reported in families of children with autism using a parent interview and assessed autism symptoms, verbal, nonverbal, and adaptive skills in a sample of 229 SIBS. Multiple regression analyses were used to examine links between family history and phenotypic outcomes, while controlling for birth year, age, sex, demographics, and parental education.

Results suggest that family history of schizophrenia, depression, anxiety, bipolar disorder, and intellectual disability associate robustly with dimensional measures of social affect, verbal and nonverbal IQ, and adaptive functioning in the SIBS. Considering family history of these disorders may improve efforts to predict long-term outcomes in younger siblings of children and inform about biological and nonbiological familial factors contributing to variable phenotypic outcomes in this cohort.

Lay summary

The study examined if family history of psychiatric and neurodevelopmental conditions is related to developmental outcome of younger siblings of children with autism spectrum disorder. The results suggest that family history of anxiety disorders, schizophrenia, bipolar disorder, depression, and intellectual disability associates with social symptom severity, verbal and nonverbal functioning, and adaptive skills in the younger siblings, regardless of their diagnostic outcome. Considering family history of psychiatric conditions and intellectual disability may help predicting important developmental outcomes in this cohort.

Introduction

Autism spectrum disorder (autism) is a neurodevelopmental condition characterized by social and communication impairments as well as sensory sensitivities, repetitive behaviors, and stereotyped interests.¹ Recent estimates place the prevalence of autism in the general population at 2.78% in the US.² Extensive evidence suggests that having a relative with autism increases the likelihood of recurrence of autism within the family, with a higher likelihood observed among relatives with greater genetic similarity.^3–5 The odds of autism are also elevated in families with a history of other neurodevelopmental (NDD) (e.g., intellectual disability (ID), attention deficit disorder (ADD), speech delays) and neuropsychiatric (NPD) (e.g., anxiety, depression, schizophrenia, and bipolar) disorders^6–10 For instance, in a large case–control study of Denmark singletons, family history of schizophrenia, ID, affective disorder, and other psychiatric disorders in the first-degree relatives was associated with higher odds of autism.⁸ A study examining NDD and NPDs history in one- to fifth-degree relatives of children in the Stockholm Youth Cohort reported that family history of ID, schizophrenia, depression, and bipolar, among others, were associated with higher odds of autism in the child.¹⁰ Emerging evidence suggests that family-based risk is not entirely explained by genetic risk, and thus, both should be considered complementary indicators of the odds of having autism.⁸

Although evidence linking family history of NDDs and NPDs with odds of autism diagnosis in the general population is robust, it is less established if family history is related to phenotypic heterogeneity in individuals with autism. Individuals with autism exhibit a broad range of symptom severity, IQ, and levels of adaptive functioning. In autism, severity of autism symptoms was associated with a higher number of psychiatric disorders in the first-degree relatives¹¹ and higher IQ was associated with family history of depression in mothers¹² and in second- and third-degree relatives.¹³ Higher IQ was also associated with family history of bipolar disorder and schizophrenia in the first-, second-, or third-degree relatives in individuals without familial history of autism.¹³ Higher adaptive skills in autism were associated with history of depression,¹² though the findings are inconsistent.¹⁴ While the findings are suggestive, there are numerous inconsistencies between the studies likely due to the marked differences in sample characteristics (e.g., some studies include only individuals with IQ>70 or only cases without family history of autism), or exclusive focus on specific family members (e.g., mothers only).

Behavioral symptoms of autism do not typically begin to manifest until the second year of life. Considering a broad interest in identification of prodromal markers of core and co-occurring features of autism, multiple studies have focused on the development of infants with family history of autism (FHA), usually defined by the presence of an older biological sibling diagnosed with the disorder.¹⁵ Due to the genetic liability, the infant siblings (SIBS) often exhibit social and communication vulnerabilities, sensory sensitivities, repetitive movements, and stereotyped interests, as well as developmental delays commonly observed in autism.^16–20 Interference levels of these characteristics vary among the SIBS; while in approximately 20% of the SIBS, the symptoms are severe and consistent with the diagnosis of autism,²¹ the remaining SIBS exhibit the intermediate symptom levels or none at all.¹⁶ Approximately 30–40% of SIBS exhibit broader autism phenotype features (i.e., social difficulties or restrictive repetitive behaviors, which do not meet the frequency or severity criteria for a full diagnosis of autism), language, or other developmental delays (cognitive, language, motor, emotional or regulatory issues).^16,22,23 Several factors have been identified as associated with diagnostic and dimensional phenotypic outcomes among the SIBS cohorts. Sex of both the sibling and the proband, ^21,24 the number of the affected siblings, presence of rare genetic copy number variations, ²⁵ and alteration in brain structure and connectivity in infancy,^26,27 associate with odds of autism diagnosis. The dimensional outcomes including symptom severity and developmental skills in the SIBS have been linked prospectively with their social attention,^28–30 joint attention and other early social-communication skills,^17,31 and motor skills exhibited in infancy,³² as well as with their older affected sibling’s symptom severity.³³ However, little is known about the contribution of family history of NDD and NPD to phenotypic outcomes observed in younger siblings of children with autism.

In the present study, we address this gap in evidence by examining the contribution of family history of several conditions common in families of individuals with autism, including intellectual disability (ID), speech delays, ADHD, anxiety, schizophrenia, bipolar, and depressive disorders⁷ to dimensional outcome measures. We focus our investigation on children with familial history of autism (FHA) defined as the presence of an older biological sibling diagnosed with autism, with most of the sample ascertained in infancy (i.e., before behavioral symptoms and delays associated with autism become apparent) and followed prospectively into the preschool and school age when the phenotypic outcomes become more stable. Rather than focusing only on those affected by autism, we aim to identify familial correlates of outcomes across the spectrum of familial risk for autism. This approach is motivated by findings that many infants with FHA who do not develop autism, nonetheless, exhibit clinically significant developmental vulnerabilities. The dimensional and cross-risk strategy adopted here is consistent with the NIMH Research Domain Criteria (RDoC) recommendations regarding the critical importance of capturing both the clinical and subclinical phenotypic variations for understanding the links between genetic factors and psychopathology.^34,35

Methods

Participants.

The study was approved by the Human Investigations Committee of Yale University School of Medicine, and informed written consent was obtained from all parents prior to testing. Participants include 229 children with at least one older biological sibling with autism. Participant characteristics including age, sex, race, ethnicity, maternal education level, and diagnosis were summarized in Table 1 . Out of 229 children, 146 (64%) were identified by their parents as male, the remaining 83 (36%) were female. The sample was recruited between March 2006 and May 2022 at an average age of 25 months (SD=46) months, with 66% of the sample recruited at or before 12 months of age and 80% before 24 months. Participants were included if they had a sibling with a clinical diagnosis of autism based on a comprehensive diagnostic assessment. Exclusionary criteria were gestational age below 34 weeks, any hearing or visual impairment, nonfebrile seizure disorders, or known genetic syndrome. The participants were categorized as American Indian or Alaska Native, Asian, Black or African American, Hispanic or Latino, Native Hawaiian or Other Pacific Islander, or White based on the NIH Policy on Reporting Race and Ethnicity Data. Children’s race and ethnicity were based on the parents’ report. In this study, 180 participants (79%) self-reported as White, 8 (4%) as Black, 13 (6%) as Asian, and 20 (9%) as multiracial. Information was not available for 8 (3%) of participants. There were 37 (16%) participants who identified as Hispanic and 178 (78%) of participants who identified as non-Hispanic; information on 14 (6%) participants was not available. Biological sex, race, and ethnicity were entered into the models as covariates of no interest.

Table 1.

Descriptive Statistics of Demographic Characteristics.

Characteristic	Descriptive Statistic
Age at recruitment (months), Mean(SD)	25 (46)
Recruited before 12 months N(%)	152 (66)
Recruited before 25 months N(%)	182 (79)
Age at family history (months), Mean(SD)	48 (52)
Age at assessment (months), Mean(SD)	64 (46)
Sex, N(%)
Male	146 (64)
Female	83 (36)
Race, N(%)
White	180 (79)
Black or African American	8 (4)
Asian	13 (6)
Multiracial	20 (9)
Not Reported	8 (4)
Ethnicity, N(%)
Non-Hispanic	178 (78)
Hispanic	37 (16)
Not Reported	14 (6)
Parental Education Level, N(%)
High school or below	19 (8)
College	76 (33)
Graduate School	129 (56)
Not Reported	5 (2.2)
Diagnosis, N(%)
Autism Spectrum Disorder	51 (22)
Broader Autism Phenotype	47 (21)
Delay or another neurodevelopmental disorder	32 (14)
Typical Development	99 (43)

Family history measure.

Family history was collected using the Family History Interview (FHI) form. The interview consisted of a series of questions pertaining to the presence of neurodevelopmental (intellectual disability, speech delays requiring therapeutic intervention, attention deficit hyperactivity disorders) and psychiatric (anxiety disorders, depression, bipolar, and schizophrenia) conditions, which are most common among FHA relatives. The interview was conducted by trained research personnel for all participants. The interviewer probed for the presence/absence of the disorders in the first-degree relatives (parents and biological siblings), second-degree relatives (half-siblings, aunts, uncles, and grandparents on the maternal and paternal side), and third-degree relatives (cousins on the maternal and paternal side). Frequency and percent of the 1st, 2nd, and 3rd degree relatives with developmental and psychiatric disorders in our sample was summarized in Table 2.

Table 2.

Frequency (percent) of siblings (n=229) with first, second, and third-degree relatives with neurodevelopmental and psychiatric disorders.

Family History Variable	Any relative N (%)	First-degreea relatives, N (%)	Second-degreeb relatives N (%)	Third-degreec relatives, N (%)
Autism Spectrum Disorder	229 (100)	229 (100)	12 (5.2)	32 (14.0)
Intellectual Disability	26 (11.4)	11 (4.8)	12 (5.2)	9 (3.9)
Speech Delay	146 (63.8)	123 (53.7)	23 (10.0)	31 (13.5)
ADHD	93 (40.6)	58 (25.3)	30 (13.1)	28 (12.2)
Anxiety Disorders	101 (44.1)	62 (27.1)	54 (23.6)	12 (5.2)
Schizophrenia	19 (8.3)	4 (1.8)	13 (5.7)	2 (0.9)
Depression	99 (43.2)	44 (19.2)	74 (32.3)	9 (3.9)
Bipolar Disorder	40 (17.5)	7 (3.1)	28 (12.2)	9 (3.9)

^aFirst-degree relative: biological parents and siblings

^bSecond-degree relative: half-siblings, aunts, uncles, grandparents

^cThird-degree relative: cousins

Taking advantage of the longitudinal nature of the study, if multiple history interviews were completed over the course of the study duration, the most recent history form was analyzed. This allowed for inclusion of the most-up-to-date history information for each participant. On average, the FHI data were collected at 48 (SD=52) months. As in other studies,^8,10,13 we quantified family history of a given disorder in a binary fashion (0/1) regardless of the degree of familial relatedness. This dichotomous approach is less likely to be influenced by differences in family size and is often used when conditions of interest have a relatively low prevalence. Thus, the final score analyzed here captures the presence of a given disorder in the family regardless of the degree of genetic similarity or the number of affected individuals. For instance, a child may have two family members with ID (e.g., a cousin and a grandparent), but the score for ID for the child would be 1.

Phenotypic outcome measures.

Autistic features were quantified using the Autism Diagnostic Observation Schedule-2 (ADOS-2) Social Affect (SA) and Restrictive and Repetitive Behaviors (RRB) calibrated scores.³⁶ The SA and RRB scores range from 0 to 10. Verbal and nonverbal IQ were quantified using the Differential Ability Scale -III (DAS-III)³⁷ or, if a child was too young or too delayed for the DAS-III administration, with the Mullen Scales of Early Learning (MSEL).³⁸ The MSEL verbal and nonverbal scale age equivalents were averaged, standardized by chronological age, and multiplied by 100, resulting in a verbal and nonverbal DQ, which served as a proxy for an IQ score in younger children. Out of 222 participants with valid IQ data, 44% contributed the DAS-III data and 56% the MSEL data to the IQ measure. Adaptive functioning was assessed using a parent interview, the Vineland Adaptive Behavior Scales (VABS-II),³⁹ and standard scores in the Communication and Socialization domains were analyzed. The IQ and VABS-II standard scores have a mean of 100 and a standard deviation of 15. Mean and standard deviation for the sample’s phenotypic outcome measures are described in Table S1. Additionally, frequency distributions of the core phenotypic outcome measures were presented (Figure S1).

Diagnostic classification.

Phenotypic characterization data reported here were collected during the most recent research study visit at an average age of 64 (SD=46) months. The clinical best estimate (CBE) diagnosis was completed by expert licensed clinicians on staff and was based on a review of developmental and medical history, direct assessment data (IQ/Developmental tests, ADOS-2), and adaptive skills (VABS-II).

Statistical analysis.

The association between family history indices and phenotypic outcome measures were analyzed using multivariate linear regression analysis with and without the following covariates child’s birth year, sex, race, ethnicity, and parental education (see Table 3 and Table S2). Year of visit was included to control for secular trends in the population related to potential changes in referral, diagnostic, and intervention practices over time. Age at outcome assessment was included to account for potential differences in levels of functioning associated with chronological. Sex was included given robust differences in phenotypic outcomes among the male and female SIBS. Demographic characteristics were included as the well-recognized contributors to developmental outcomes. For each regression analysis, beta estimates and p-values are presented in corresponding table. The statistical significance threshold, alpha, was set to .05 (5%). Further, 95% confidence intervals are provided for adjusted multivariate linear regression analyses (Table S3). For each regression, to estimate the effect size in terms of the proportion of variance explained by the family history variables in the presence of the covariates, Cohen’s F² was calculated.⁴⁰ Per Cohen’s guidelines, an f² of  ≥ 0.02, represents a small effect size, f² ≥ 0.15 medium and f² ≥ 0.35 large effect.⁴⁰ Statistical analyses were performed using R statistical software, version 4.3.1.

Table 3.

Multilinear regression analysis evaluating associations between family history and phenotypic outcomes in younger siblings of children with autism, adjusted for age, sex, race, ethnicity, parental education, and birth year.

	ADOS-2 SA		ADOS-2 RRB		Verbal IQ		Non-Verbal IQ		VABS-II Communication		VABS-II Socialization
R2	0.17		0.12		0.32		0.25		0.29		0.18
R2 accounted for family variables	0.07		0.05		0.17		0.14		0.14		0.10
Cohen’s F2	0.12		0.06		0.19		0.12		0.13		0.12
	Beta	P-Value	Beta	P-Value	Beta	P-Value	Beta	P-Value	Beta	P-Value	Beta	P-Value
Intellectual Disability	0.81	0.15	1.27	0.05	−16.15	0.002	−12.29	0.005	−9.55	0.02	−5.35	0.15
Speech Delay	−0.32	0.35	0.31	0.45	0.72	0.82	1.11	0.68	−2.05	0.41	0.75	0.74
ADHD	−0.36	0.29	−0.32	0.43	5.34	0.10	4.50	0.10	2.50	0.31	1.77	0.44
Anxiety Disorders	0.92	0.01	0.60	0.16	−13.18	<.001	−8.11	0.005	−8.10	0.002	−7.02	0.004
Schizophrenia	1.82	0.005	1.36	0.07	2.55	0.66	0.83	0.87	−0.79	0.86	−7.83	0.07
Depression	−0.29	0.43	−0.32	0.46	10.45	0.003	6.57	0.03	5.78	0.03	4.10	0.10
Bipolar Disorder	0.33	0.49	0.32	0.57	−4.49	0.30	−3.22	0.39	−6.86	0.047	−6.18	0.05
Age (continuous)	−0.005	0.22	<.001	0.93	−0.03	0.44	−0.06	0.07	−0.08	0.01	0.07	0.01
Race (ref= white)	0.31	0.48	−0.35	0.49	−2.58	0.52	−1.84	0.59	−2.01	0.52	1.59	0.58
Sex (ref=male)	−1.21	<.001	−1.50	<.001	12.13	<.001	8.38	0.002	8.34	0.001	5.31	0.02
Parental education (ref=high school)	1.00	0.10	0.60	0.40	8.30	0.14	3.83	0.42	0.58	0.90	−1.46	0.72
Ethnicity (ref=non-Hispanic)	0.64	0.16	0.21	0.69	−13.94	0.001	−4.64	0.20	−10.96	0.001	−3.79	0.21
Birth Year (continuous)	0.005	0.92	0.04	0.51	−1.41	0.003	−1.53	<.001	−1.21	0.001	−0.44	0.18

RESULTS

Preliminary Analysis

Diagnostic outcomes.

Based on the comprehensive assessments, 51 (22%) children received diagnosis of autism, 79 (35%) exhibited broader autism phenotype features (BAP) signaling presence of milder or isolated social-affective or RRB symptoms that do not cross the diagnostic threshold specified in the DSM-5 or other clinically significant concerns including ADHD, anxiety, language delays, or global delays with varied degrees of severity (ATP), and 99 (43%) had typical outcomes (TYP). These proportions are consistent with other reports regarding developmental outcomes in SIBS cohorts²¹ and highlight the heterogeneity of the phenotypic outcomes in this population. The SIBS with and without autism diagnosis did not differ in the age of recruitment (F(1, 228) = 1.99, p=.160), nor did they differ in the age of the phenotypic assessment (F(1, 226) = 1.59, p=.21).

Prevalence of neurodevelopmental and psychiatric conditions.

The proportions of siblings with a family history of NDDs and NPDs in the first-, second-, and third-degree relatives are presented in Table 2. Given the inclusion criteria, all participants had a family history of autism in the first-degree relatives, and some also had second- and third-degree family members with autism. Among NDDs, the most frequently reported condition was speech delay requiring therapy (64%), followed by ADHD (41%) and ID (11%). Among NPDs, the most common were anxiety disorders (44%), depression (43%), bipolar disorder (17%), and schizophrenia (8%). The prevalence of a family history of psychiatric and neurodevelopmental disorders observed in the SIBS group was largely consistent with prevalence of the disorders reported in families with individuals with autism.¹¹

Primary Analysis

Family history and autism symptom severity.

Family history variables accounted jointly for 7% and 5% of variability in the ADOS-2 SA and RRB scores, respectively, after controlling for the effects of covariates. SA scores were higher in SIBS with a family history of anxiety disorders [β = 0.92; 95% CI, 0.21 to 1.63; P = 0.01], and schizophrenia [β = 1.82; 95% CI, 0.57 to 3.07; P=0.005] (see Figure 1, and Table 3; see also Table S3 for information regarding 95% confidence intervals for all effects). Although the associations were less precise, the RRB scores were higher in SIBS with a family history of ID [β = 1.27; 95% CI, −0.001 to 2.55; p=0.05]. Thus, family history of an anxiety disorder and schizophrenia was associated with an increase in severity of social affective autistic features by an average of 0.92 and 1.83 points, respectively, measured on a 0–10 scale. There was also a trend toward higher severity of the RRB characteristics in those with a family history of ID, with increases of an average 1.27 on a 0 to 10 scale.

Figure 1.

Estimates and confidence intervals for multilinear regression analysis evaluating associations between family history variables and ADOS–2 SA and RRB scores. Adjusted for birth year, age, sex, race, ethnicity, and parental education.

Family history and verbal and nonverbal IQ.

Family history variables accounted for 17% and 14% of variance in the verbal and nonverbal IQ scores. Verbal IQ was inversely associated with a family history of ID [β = −16.15; 95% CI, −26.17 to −6.14; P=0.002] and anxiety disorders [β = −13.18; 95% CI, −19.76 to −6.60; P<.001], and positively associated with history of depression [β = 10.45; 95% CI, 3.71 to 17.20; P=0.003] (see Figure 2). Nonverbal IQ was inversely associated with a family history of ID [β = −12.29; 95% CI, −20.88 to −3.70; P=0.005] and anxiety disorders [β = −8.11; 95% CI, −13.74 to −2.48; P=0.005] and positively associated with history of depression [β = 6.57; 95% CI, 0.78 to 12.36; P=0.03]. Having a relative with ID or an anxiety disorder was linked with an average decrease in verbal IQ scores by 16 and 13 points, respectively, measured on a scale with a mean of 100 and standard deviation of 15. Similarly, family history of ID and an anxiety disorder aggregated with an average decrease in nonverbal IQ by 12 and 8 points, respectively. In contrast, history of depression aggregated with higher verbal and nonverbal IQ with mean estimates of 10 and 7 points, respectively.

Figure 2.

Estimates and confidence intervals for multilinear regression analysis evaluating associations between family history variables and verbal and nonverbal IQ. Adjusted for birth year, age, sex, race, ethnicity, and parental education.

Family history and adaptive functioning.

Family history variables accounted for 14% and 10% of variance in the VABS-II Communication and Socialization standard scores. The VABS-II Communication scores were negatively associated with familial history of ID [β = −9.55; 95% CI, −17.35 to −1.74; P=0.02], anxiety disorders [β = −8.10; 95% CI, −13.22 to −2.98; P=0.002], and bipolar [β = −6.86; 95% CI, −13.62 to −0.11; P=0.05] disorders (see Figure 3). However, history of depression was associated with higher VABS-II Communication scores, [β = 5.78; 95% CI, 0.58 to 10.99; P=0.03]. In comparison, the VABS-II Socialization scores were inversely associated with a family history of anxiety disorders [β = −7.02; 95% CI, −11.76 to −2.27, p=0.004]. They were also associated negatively with schizophrenia [β = −7.83; 95% CI, −16.17 to 0.51], P=0.07] and bipolar [β = −6.18; 95% CI, −12.44 to 0.08, P=0.05], though the estimate was less precise and included the null. Family history of ID, an anxiety disorder, and bipolar disorder aggregated with lower adaptive communication levels by an average of 10, 8, and 7 points, respectively, on a scale with a mean of 100 and standard deviation of 15. Lower adaptive socialization scores were associated with family history of an anxiety disorder (a mean 7-point decrease); there was also a trend toward lower scores with history of schizophrenia (a mean 8-point decrease) and bipolar (a mean 6-point decrease). History of depression was associated with higher VABS-II Communication scores by an average of 6 points.

Figure 3.

Estimates and confidence intervals for multilinear regression analysis evaluating associations between family history variables and VABS-II Communication and Socialization scores. Adjusted for birth year, age, sex, race, ethnicity, and parental education.

DISCUSSION

Atypical social and repetitive behaviors as well as delays in verbal, nonverbal, and adaptive skills are common among siblings of children with autism. The present study demonstrates, for the first time, that the phenotypic dimensional outcomes in the younger siblings associate with family history of anxiety, depression, schizophrenia, and bipolar disorders as well as intellectual disability. While some disorders aggregate with lower levels of functioning, others were linked with more optimal phenotypic outcomes. After controlling for the influence of covariates, the family history of NDDs and NPDs accounted for approximately 5% to 17% of variance across the outcome variables, with the magnitude of estimated effect sizes ranging from small to medium.

Among the younger siblings, family history of an anxiety disorder, schizophrenia, and ID aggregated with an increase in severity of social affective characteristics common in autism, amounting to a 9–18% shift toward the higher ADOS-2 social affect values. The estimates were less precise for the restrictive and repetitive behaviors, but the analysis implicated intellectual disability as a potential correlate of symptom severity in this domain. Although a prior study linked a combined history of NDDs and NPDs with higher symptom severity in autism,¹¹ here we identify specifically anxiety disorders and schizophrenia as significant correlates of the variability in severity of core social affective symptoms in SIBS. Family history of anxiety and intellectual disability were associated, with a half to a full standard deviation shifts in scores toward lower values in verbal and nonverbal IQ and adaptive functioning. Interestingly, family history of depression associated with higher IQ and adaptive communication scores, which is consistent with several prior studies.^12,13,41 These findings suggest that considering family history of psychiatric and neurodevelopmental disorders alongside other previously identified predictors including the sibling sex,²¹ social attention^28–30 social-communication skills,^17,31 and motor skills³² as well as the older sibling’s functional skills,³³ may improve predictive modeling of phenotypic outcomes of infant siblings of children with autism.⁴²

The study reveals potential associations between family history and outcomes in younger siblings of children with autism, but the nature of these associations remains to be clarified. It is plausible that the genetic factors that give raise to NDDs and NPDs in the family members are also present in the SIBS and therefore impart their influence on their social, cognitive, and adaptive skill development. In addition to genetic factors, familial-environmental factors may also play a role. Having a relative with a neurodevelopmental or psychiatric condition may alter the family dynamics, child rearing practices, or enhance likelihood of environmental exposures in the child,^43–45 which may further affect the child’s development either in a positive or negative manner. Presence of genetic risk may also enhance vulnerability to environmental adversities shared by family members^46,47 Finally, parental mental health during pregnancy may also have long-term effects of child development through epigenetic programming.⁴⁸ Future studies will be necessary to disambiguate the mechanistic underpinnings of the observed associations. Despite lack of clarity of the mechanisms underlying the observed effects, family history of selected psychiatric and developmental disorders signals increased developmental vulnerabilities in this cohort.

Limitations.

The study has several limitations. Information regarding family history was based on an interview with a single informant (a parent) rather than with both parents or multiple family members, and thus, it is plausible that certain disorders, especially in more distant relatives may have been under-reported. Even with this limitation, the family history method has been widely used and has shown high validity and reliability in the past studies.^49,50 Another limitation may stem from potential ascertainment biases which may arise from systematic variation in probabilities of study participation as a function of family history and child characteristics. For instance, anxious parents may be more likely to participate in a study that offers developmental monitoring of an offspring. The opposite, however, may also be true, when the presence of psychiatric conditions in a parent or another family member may lower the likelihood of study participation due to e.g., increased commitments or other limitations. Furthermore, parents of children with more extensive delays and presumably, greater genetic load, may be more likely to enroll their children into the study. However, a majority (62%) of the sample was enrolled in infancy before 12 months of age, which is early for delays to be apparent in the SIBS samples and cases with known genetic abnormalities were excluded from the study. Notably, the distribution of diagnostic outcomes and levels of functioning in our cohort is consistent with that reported in other prospective infant sibling studies²¹ and that the prevalence of psychiatric and neurodevelopmental disorders observed our sample is consistent with reports based on larger community-based samples.¹¹ The study is focused on participants with the first-degree relatives, though, future work would need to determine if the findings extend to children in whom the family history of autism involves more distant relatives (e.g., aunts and uncles).³ Finally, the demographic distribution of the sample is skewed toward White, Non-Hispanic, and college-educated parents, and although within the sample, the effect estimates of these factors on the outcomes were largely negligible, a replication in a more diverse sample will be necessary.

Conclusions.

The study demonstrates, for the first time, that presence of anxiety disorders, schizophrenia, ID, depression, and bipolar disorders in family members associate with the highly heterogenous behavioral phenotypes observed in younger siblings of children with autism. Recording family history already constitutes a critical element in pediatric medicine.^51,52 Considering family history of NDD and NPD may improve efforts to predict long term outcomes in the infants siblings and to improve identification of the infants with the greatest risk for exhibiting developmental vulnerabilities regardless of the diagnostic outcome. More broadly, the study highlights the need for monitoring development of infants with family history of neurodevelopmental and psychiatric conditions to optimally support their development across multiple domains. The results motivate further investigations into genetic and family factors that may affect developmental outcomes in the siblings that extend beyond the genetic liability for autism diagnosis.

Abbreviations:

ADOS-2

Autism Diagnostic Observation Scale-Second Edition

VABS-II

Vineland Adaptive Behavior Scales-Second Edition

FHA

Family history of autism

NDD

Neurodevelopmental Disorders

NPD

Neuropsychiatric Disorders

MSEL

Mullen Scales of Early Learning

DAS-III

Differential Ability Scale-Third Edition

ID

Intellectual Disability

ADHD

Attention Deficit and Hyperactivity Disorder