Non-Isolated Dandy-Walker Malformation: Exome Sequencing Efficacy and Phenotypic Expansions

Area of Science:

• Genetics
• Neuroscience
• Developmental Biology

Background:

• Dandy-Walker malformation (DWM) is a rare congenital hindbrain developmental anomaly.
• DWM frequently occurs with other central nervous system (CNS) or extra-CNS abnormalities (DWM+).
• Molecular causes for DWM+ remain largely unidentified due to suboptimal genetic testing strategies.

Purpose of the Study:

• To evaluate the diagnostic efficacy of clinical exome sequencing (cES) for individuals with DWM+.
• To identify novel genetic causes and phenotypic expansions associated with DWM.
• To guide optimal genetic testing strategies for DWM+.

Main Methods:

• Analysis of clinical exome sequencing (cES) data from 91 individuals diagnosed with DWM+.
• Comparison of cES diagnostic yield against standard brain malformation gene panels.
• Integration of cohort data, published cases, and mouse models to identify phenotypic expansions.

Main Results:

• cES achieved a diagnostic rate of 35.2% (32/91) in individuals with DWM+.
• Standard gene panels detected only 24.2% to 54.5% of diagnoses identified by cES.
• Nine phenotypic expansions associated with DWM were identified.

Conclusions:

• cES is a powerful tool for diagnosing DWM+ and should be considered when molecular diagnoses are not established.
• Routine additional genetic testing may not be necessary for DWM+ patients with identified genetic syndromes.
• This study expands the understanding of genetic causes and phenotypes related to DWM.