Mendelian gene identification through mouse embryo viability screening.

Area of Science:

• Genetics and Genomics
• Developmental Biology
• Rare Diseases

Background:

• Advancing Mendelian disorder diagnostics relies on novel gene discovery.
• Interpreting variants in uncharacterized genes is challenging.
• Combining functional genomics with phenotypic similarity aids gene discovery.

Purpose of the Study:

• To refine the spectrum of gene essentiality by analyzing embryonic lethality timing in mice.
• To correlate embryonic lethality windows with gene features and human disease phenotypes.
• To explore gene similarity for novel disease gene discovery in unsolved rare disease cases.

Main Methods:

• Classified lethal genes based on embryonic lethality timing (early, mid, late gestation) in mouse knockouts.
• Analyzed gene features (developmental expression, paralogy, constraint) and human disease phenotypes.
• Investigated unsolved cases from the 100,000 Genomes Project using gene similarity approaches.

Main Results:

• Early gestation lethal genes are enriched for those associated with recessive inherited metabolic diseases.
• Identified candidate genes with features similar to known inborn errors of metabolism.
• Found enrichment of pathogenic variants in early gestation lethal genes within patients having metabolic disease categories.

Conclusions:

• Embryonic lethality timing in knockout mice can guide novel disease gene discovery.
• This approach aids in prioritizing variants for unsolved rare disease cases.
• Highlights potential novel gene candidates for specific inherited metabolic disorders.