Assortative mating and parental genetic relatedness contribute to the pathogenicity of variably expressive variants.

This research looked at nearly 100,000 families to understand how parents' traits affect their children's neurodevelopmental conditions like autism. The study found that parents and children often share similar characteristics, and that parents with mild autism-like traits tend to have children with more severe autism symptoms. It also showed that couples often have similar mental health traits, which can increase the risk of conditions in their children over generations.

This large-scale study examined over 97,000 families across four neurodevelopmental disease cohorts and the UK Biobank to understand how parental characteristics contribute to neurodevelopmental conditions in children. Researchers found significant correlations between parent and child phenotypes, including autism features and various psychiatric conditions. The study revealed that spouses often share similar neurological and psychiatric traits (assortative mating), which can increase disease liability across generations. Parents' subclinical autism features correlated with autism severity measures in their children.

Additionally, parental genetic relatedness was identified as a risk factor, potentially through increased genome-wide homozygosity in offspring. The findings suggest that assessing both parental phenotypes and genotypes could help predict clinical features in children carrying rare genetic variants.

Findings suggest that comprehensive assessment of parental phenotypes and genotypes could improve prediction of clinical features in children with rare genetic variants. This may inform genetic counseling approaches and early intervention strategies. The identification of assortative mating patterns could help identify families at higher risk for severe neurodevelopmental outcomes.

The study type is not specified, and specific sample sizes for individual analyses are not reported. The abstract does not detail methodology, control measures, or potential confounding factors. The clinical significance of correlation coefficients and their translation to practical outcomes requires further clarification.

We examined more than 97,000 families from four neurodevelopmental disease cohorts and the UK Biobank to identify phenotypic and genetic patterns in parents contributing to neurodevelopmental disease risk in children. We identified within- and cross-disorder correlations between six phenotypes in parents and children, such as obsessive-compulsive disorder (R = 0.32-0.38, p < 10). We also found that measures of sub-clinical autism features in parents are associated with several autism severity measures in children, including biparental mean Social Responsiveness Scale scores and proband Repetitive Behaviors Scale scores (regression coefficient = 0.14, p = 3.38 × 10). We further describe patterns of phenotypic similarity between spouses, where spouses show correlations for six neurological and psychiatric phenotypes, including a within-disorder correlation for depression (R = 0.24-0.68, p < 0.001) and a cross-disorder correlation between anxiety and bipolar disorder (R = 0.09-0.22, p < 10).

Using a simulated population, we also found that assortative mating can lead to increases in disease liability over generations and the appearance of "genetic anticipation" in families carrying rare variants. We identified several families in a neurodevelopmental disease cohort where the proband inherited multiple rare variants in disease-associated genes from each of their affected parents. We further identified parental relatedness as a risk factor for neurodevelopmental disorders through its inverse relationship with variant pathogenicity and propose that parental relatedness modulates disease risk by increasing genome-wide homozygosity in children (R = 0.05-0.26, p < 0.05). Our results highlight the utility of assessing parent phenotypes and genotypes toward predicting features in children who carry rare variably expressive variants and implicate assortative mating as a risk factor for increased disease severity in these families.