Resolving Diagnostic Uncertainty in Neurodevelopmental Disorders Using Exome Sequencing Supported by Literature-Based...

Area of Science:

• Genetics
• Neuroscience
• Bioinformatics

Background:

• Neurodevelopmental disorders (NDDs) are genetically complex, with exome sequencing (ES) as a primary diagnostic method.
• Interpreting variants of uncertain significance (VUSs) and inherited variants with incomplete penetrance remains a clinical challenge.
• Multi-omics data can aid in the interpretation of novel and rare variants for NDDs.

Purpose of the Study:

• To assess the utility of integrating multi-omics evidence for interpreting rare genetic variants in patients with NDDs.
• To evaluate challenges in variant classification, including VUSs and incomplete penetrance.
• To explore the diagnostic yield of exome sequencing in a cohort of NDD patients.

Main Methods:

• Exome sequencing (ES) and segregation analysis were performed on 20 patients with NDDs and their parents.
• Variants were classified using ACMG/ACGS guidelines, with literature review and multi-omics data integration.
• Gene-level constraint metrics, in silico predictions, and transcriptomic/proteomic data were utilized.

Main Results:

• Twenty rare variants were identified across 18 NDD-associated genes (3 pathogenic, 9 likely pathogenic, 8 VUSs).
• Challenges with incomplete penetrance were noted for inherited variants in genes like KMT5B, TANC2, SPTBN1, and CHD4.
• Multi-omics evidence supported the interpretation of several VUSs, and two patients had dual molecular diagnoses.

Conclusions:

• Interpreting VUSs and inherited variants in NDDs continues to be a significant clinical hurdle.
• Integrating genomic data with published multi-omics evidence enhances variant interpretation and diagnostic confidence.
• Broader adoption of multi-omics approaches is recommended for evaluating rare NDDs.