Increased Presence of Familial Psychiatric and Neurodevelopmental Disorders in Groups with Unclear or Negative Autism Spectrum Disorder Diagnosis in a State-Wide Autism Registry

Background: Family history is important to consider in patients with Autism Spectrum Disorder (ASD) as literature has shown increased presence of familial psychiatric disorders compared to the general population. Psychiatric comorbidity is also high in ASD and associated with functional impairment and increased diagnostic challenges (Leyfner et al. 2006; Molloy et al. 2011). Disorders that are especially prevalent in these families include depression, bipolar, and anxiety disorders (Cohen & Tsiouris, 2006; Micali et al., 2004).

Objectives: To investigate differences in family psychiatric and neurodevelopmental history in individuals referred to an ASD research registry grouped by level of diagnostic confirmation and confidence.

Methods: Participants were the first 1,000 individuals enrolled in a state-wide autism registry (Male = 780; M_age = 13.6 years, SD = 9.6). Referrals were based on existing diagnosis or concern for ASD. Participants were categorized into three groups: (1) ASD (N = 533): having a community diagnosis of ASD confirmed by the ADOS-2; (2) ASD-unclear (N = 318): having an inconsistency between community diagnosis and ADOS-2 result; and (3) non-ASD (N = 101): having a negative ADOS and no community diagnosis. Family history was obtained by interview. Analyses examined group differences of individual disorders as well as composite scores of total number of neurodevelopmental and psychiatric disorders.

Results: Using one-way ANOVA and Tukey post-hoc tests, controlling for false-discovery rate, there was increased presence of multiple psychiatric and neurodevelopmental disorders in non-ASD and ASD-unclear groups as compared to ASD group. The overall number of psychiatric disorders in first-degree relatives was significantly higher in ASD-unclear (M = 2.15, SD = 2.05, F ((2, 862) = 14.0, p < .001) and non-ASD (M = 2.42, SD = 2.35, p < .001) as compared to ASD (M = 1.56, SD = 1.66). The non-ASD group reported more neurodevelopmental disorders in first-degree relatives (M = 1.62, SD = 1.70, p = .013) than the ASD group (M = 1.11, SD = 1.48). Follow-up analysis showed that probands in ASD-unclear (M= 2.3, SD = 1.7) and non-ASD groups (M= 2.5, SD = 1.7) had increased psychiatric comorbidities as compared to ASD group (mean = 1.58, SD = 1.5, F (3,546) = 16.1, p < .001). There was a significant positive correlation between number of psychiatric diagnoses in the proband and number of psychiatric disorders in first-degree relatives (r = .28, N = 550, p <.001). A linear regression was performed controlling for biologic sex and age (R² = 0.13, F (3, 546) = 25.92, β = .27, t = 6.8, p < .001), that confirmed a statistically significant association between number of first-degree family diagnoses and number of proband comorbidities.

Conclusions: Individuals in the ASD group had less family members affected with neurodevelopmental or psychiatric disorders and less psychiatric comorbidities as compared to ASD-unclear and non-ASD groups. This finding supports that registry referrals of ASD-unclear and non-ASD individuals are in part due to more complicated psychiatric presentation, and demonstrates the need for clinical tools that can aid in differentiating these groups.