Systematic Review: White Matter Microstructure and Structural Connectivity in Offspring at Familial High-Risk for Severe Mental Illness

Objective Parental severe mental illness (SMI), such as schizophrenia, bipolar disorder, or major depressive disorder, is among the strongest risk factors for offspring psychiatric disorders. Yet it remains unclear how familial high-risk is expressed in white-matter tracts that are highly heritable and undergo rapid change during childhood and adolescence. This systematic review synthesizes diffusion magnetic resonance imaging (dMRI) findings in offspring of parents with schizophrenia (SZo), bipolar disorder (BDo) and major depressive disorder (MDDo). Method This review was preregistered on PROSPERO (CRD420251067140). Following PRISMA guidelines, systematic searches were conducted in Embase, PubMed, Web of Science, and PsycINFO (July 19, 2025). Eligible studies included dMRI data from offspring <18 years at first scan, with parental SMI confirmed by diagnostic interview, and controls with unaffected parents. Results Thirty-one studies (17 cohorts; N =1,704 familial high-risk offspring, N =1,572 controls) met inclusion criteria. Across disorders, microstructural alterations appeared mostly in fronto-limbic (cingulum, uncinate fasciculus, corpus callosum) and fronto-parietal/projection (superior longitudinal fasciculus, corona radiata) tracts. Fractional anisotropy (FA) was typically lower in SZo and MDDo, whereas BDo showed mixed findings, with a tendency toward lower FA in affected BDo. Structural connectivity findings were sparse and inconclusive. Conclusion Familial high-risk for SMI is associated with altered fronto-parietal, limbic, and callosal white matter tracts during adolescence irrespective of parental diagnosis, which support emotion regulation, cognitive control, and interhemispheric integration. Despite directional heterogeneity in BDo, these tracts may act as potential early markers of vulnerability. Harmonized, longitudinal, and multimodal approaches are needed to clarify developmental timing, identify markers of transition to illness, and inform early preventive interventions.