Integrating a Transdiagnostic Clinical Approach with Whole-Exome Sequencing in Neurodevelopmental Disorders: A Single-Center Exploratory Study

AI Summary

Data-driven clinical profiling produced four profiles (C1–C4) with 89.1% high-confidence assignment and revealed pathway enrichment distinct from diagnoses.
Both groupings implicated Transcriptional Regulation by MECP2, found in profile C3 (social-sensory/repetitive) and in the ADHD diagnostic group.
Reported associations did not survive multiple testing and require independent replication plus functional or epigenomic validation.

TL;DR (AI Generated)

We investigated whether grouping patients by data-driven clinical profiles rather than by diagnosis points to different biological pathways.

Methods: We retrospectively evaluated a single-center cohort of 128 patients, grouping them into diagnosis and genetics-independent clinical profiles and into six overlapping DSM-5 diagnostic groups.

The profiles yielded one enriched pathway, Transcriptional Regulation by MECP2 in profile C3 Social-Sensory/Repetitive (IRR 1.46, 95% CI 1.06-2.03; p = 0.0223); the diagnoses yielded 21, including the same pathway, which emerged in ADHD rather than in ASD, the diagnosis closest to C3.

Basic summary

Diagnostics (Basel). 2026 Nov 6;16(21):3674. doi: 10.3390/diagnostics16213674.

ABSTRACT

Background/Objectives: Neurodevelopmental disorders overlap in cognitive, language, motor, behavioral and social-communication features and vary widely in their genetic causes, which limits etiological research and patient stratification. We investigated whether grouping patients by data-driven clinical profiles rather than by diagnosis points to different biological pathways. Methods: We retrospectively evaluated a single-center cohort of 128 patients, grouping them into diagnosis and genetics-independent clinical profiles and into six overlapping DSM-5 diagnostic groups. In each group, the genes carrying a causative variant found by whole-exome sequencing were linked to the biological pathways they belong to. Data on variants of uncertain significance (VUS) were available for 113 of the 128 patients, in whom we counted VUS in these pathways. Each group was compared with the other patients by Poisson regression accounting for each patient’s total VUS count. Analyses were repeated in patients with high-confidence profile assignments. Results: Four clinical profiles were identified (labeled C1-C4), and 89.1% of patients were assigned to one with high confidence. A pathway was considered enriched in a group when the group’s patients carried more VUS in it than other patients (p < 0.05, uncorrected). The profiles yielded one enriched pathway, Transcriptional Regulation by MECP2 in profile C3 Social-Sensory/Repetitive (IRR 1.46, 95% CI 1.06-2.03; p = 0.0223); the diagnoses yielded 21, including the same pathway, which emerged in ADHD rather than in ASD, the diagnosis closest to C3. In the high-confidence subset, Myogenesis appeared in C4 Motor-Neurological, with no diagnostic counterpart. No association survived multiple testing. Conclusions: The two groupings proved complementary rather than alternative: both pointed to Transcriptional Regulation by MECP2, and each raised hypotheses the other missed. All these hypotheses require independent replication and functional or epigenomic validation.

PMID:43028545 | DOI:10.3390/diagnostics16213674

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