Configuration-Level Genetic Interpretation in Neurodevelopmental Disorders: A Single-Center Cohort of 2162 Children...

Background/Objectives: Compound heterozygosity, multilocus molecular diagnoses, mosaicism, uniparental disomy (UPD), and mitochondrial DNA (mtDNA) heteroplasmy are established configuration-dependent diagnostic categories whose interpretation requires consideration of allelic phase, dosage, parental origin, and tissue distribution. This study evaluated their diagnostic contribution and clinical characteristics in pediatric neurodevelopmental disorders (NDDs). Methods: This single-center retrospective cohort study conducted a descriptive cross-phenotypic evaluation of 2162 children in China who underwent clinical genetic testing between 2015 and 2024. The primary analysis focused on confirmed diagnostic configurations, whereas study-defined possibly diagnostic configurations were included only in expanded-set sensitivity and supplementary descriptive analyses. Binary clinical outcomes were adjusted for sex, calendar year of testing, and primary testing strategy. Ascertainment depended on the genetic tests performed for each child rather than systematic screening for all five categories. Results: Confirmed diagnostic configurations were identified in 166/1009 (16.5%) children with definitive molecular diagnoses, corresponding to 166/2162 (7.7%) of the full cohort. These comprised 103 compound heterozygous configurations, 24 multilocus molecular diagnoses, 19 mosaic findings, 4 UPD-related configurations, and 16 mtDNA heteroplasmy configurations. An additional 34 children had possibly diagnostic configurations, yielding an expanded configuration set of 200/2162 (9.3%), which was not interpreted as a definitive diagnostic yield. In the confirmed-only analysis, age at onset was lower than in the comparison group (median 1.80 vs. 2.80 years, Bonferroni-adjusted p = 0.008), and epilepsy was less frequent [94/166 (56.6%) vs. 1338/1962 (68.2%), Bonferroni-adjusted p = 0.035]. Conclusions: Confirmed diagnostic configurations involving these five categories accounted for 16.5% of definitive molecular diagnoses and were characterized by a lower frequency of epilepsy at the cohort level. Configuration-level assessment of allelic phase, dosage, multilocus contribution, parental origin, mosaic fraction, and tissue context may improve diagnostic completeness and recurrence-risk counseling.