Authors :
Presenting Author: Ludovica Montanucci, PhD – Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
Tobias Brünger, PhD – Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
Christian Bosselmann, MD – Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany
Costin Leu, PhD – McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
Dennis Lal, PhD – Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
Rationale: Although >1,000 genes are implicated in neurodevelopmental disorders and epilepsies (NDD/EPI), most genotype-phenotype studies provide only single-time-point snapshots without matched comparison groups. Thus, the broad variability in age of onset and clinical expressivity remains unmapped, and gene-specific trajectories of symptom evolution and comorbidity are undefined, blunting prognostic accuracy. Here, we analyze natural history data of the globally largest cohort of monogenic NDD/EPI to overcome these limitations in genetic informed care.
Methods: We queried the Simons Searchlight registry for 2,245 individuals (0–20 yr) carrying pathogenic variants in 85 monogenic NDD/EPI genes or copy number variants. Each participant had age-of-onset data for 209 harmonized phenotypes. For every genetic disorder, we identified phenotype enrichment with Fisher’s exact tests, assessed penetrance specificity using two-proportion Z-tests, compared age-at-onset distributions via Cox proportional-hazards models, and modeled cumulative penetrance with Kaplan–Meier estimators to derive genetic disorder-resolved developmental trajectories.
Results: In the cross-disorder analyses, intellectual disability and autism were the most frequent phenotypes, occurring in 94% and 90% of 85 genetic NDD/EPIs disorders, while 61 phenotypes were rare and only reported in ≤10% genetic NDD/EPIs disorders. Ocular anomalies, hypotonia, and generalized tonic-clonic seizures (GTCS) reached ≥50 % prevalence in each NDD/EPI associated genes/CNVs. In contrast, the remaining phenotypes were only observed in less than 10% of variant carrier for an individual monogenic NDD/EPIs disorder. In the disorder specificity analyses, we detected 43 gene/CNV-phenotype enrichments, including microcephaly in
DYRK1A (OR = 32, P = 5.9 × 10⁻¹⁴), macrocephaly in
PPP2R5D (OR = 19, P = 8.4 × 10⁻³⁷), tonic seizures in
SCN2A (OR = 8, P = 3.7 × 10⁻¹²). Penetrance Z-tests flagged 28 disorders with significantly higher and nine with lower penetrance than the 85 monogenic NDD/EPI cohort average; SCN2A, SYNGAP1, SLC6A1, and STXBP1 exhibited elevated seizure penetrance, whereas the 1q21.1 duplication showed markedly reduced seizure penetrance. Cox models revealed four delayed-onset genetic disorder–phenotype pairs, including later hypotonia and cognitive delay in several CNVs and postponed GTCS in SLC6A1. For 26 genetic NDD/EPIs disorders we generated age-stratified cumulative penetrance curves -average of 25 phenotypes per disorder - providing high-resolution developmental trajectories that can inform anticipatory clinical guidance and precision genetic counseling.
Conclusions: Leveraging the largest deeply phenotyped cohort of monogenic NDD/EPI, we deliver the first cross-condition, age-aware penetrance atlas spanning 85 genetic disorders. The analysis exposes both convergent traits suitable for universal screening and sharply divergent gene-specific timelines, providing foundation for anticipatory counseling, risk-based monitoring, and rational endpoint selection in disease-modifying trials.
Funding: This work was supported by the McGovern Medical School at the University of Texas Health Science Center at Houston