A Cross-Disorder Method to Identify Novel Candidate Genes for Developmental Brain Disorders

Area of Science:

• Genetics
• Neuroscience
• Genomic Medicine

Background:

• Developmental brain disorders are genetically heterogeneous with high heritability.
• Advances in genome sequencing facilitate the identification of pathogenic variants.
• Shared genetic causes can underlie distinct phenotypic features.

Purpose of the Study:

• To identify novel candidate genes for developmental brain disorders.
• To provide evidence for previously implicated genes.
• To leverage a cross-disorder approach for enhanced gene discovery.

Main Methods:

• Searched PubMed for studies on developmental brain disorders (2003-2015).
• Employed a tiered, multilevel data-integration of whole-genome data (pathogenic loss-of-function variants) and phenotype data from six disorders.
• Prioritized genes based on inheritance patterns and the number of pathogenic loss-of-function variants in unrelated individuals.

Main Results:

• Reviewed 384 studies involving 1960 individuals with developmental brain disorders.
• Identified 241 genes with 2 or more pathogenic loss-of-function variants in at least two unrelated individuals.
• Discovered 7 novel high-confidence and 10 novel putative candidate genes, with 18 genes upgraded due to the cross-disorder approach.

Conclusions:

• The integrated, cross-disorder approach enhances gene discovery for developmental brain disorders.
• Results support shared genetic etiologies among seemingly distinct neurological conditions.
• The study underscores the significant clinical and genetic heterogeneity of developmental brain disorders.