Genotype first: Clinical genomics research through a reverse phenotyping approach.

Area of Science:

• Genomics
• Genomic Medicine
• Translational Research

Background:

• Genomic research traditionally relies on identifying diseases first, then seeking genetic causes.
• Decreasing sequencing costs enable a shift towards identifying genetic variants first, then seeking associated diseases.

Purpose of the Study:

• To describe the implementation and infrastructure for genomic ascertainment and reverse phenotyping research.
• To evaluate the utility of reverse phenotyping in discovering genotype-disease associations and understanding disease mechanisms.

Main Methods:

• Developed infrastructure to aggregate a super-cohort of sequenced individuals for recontact.
• Piloted reverse phenotyping in 13 studies at the National Institutes of Health (NIH).
• Focused on targeted phenotypic evaluations for individuals with specific genomic variants.

Main Results:

• Reverse phenotyping studies facilitated novel genotype-disease associations.
• Expanded the known phenotypic spectrum for certain genetic variants.
• Demonstrated ex vivo functional mechanisms underlying genetic diseases.

Conclusions:

• Reverse phenotyping is a powerful approach for predictive genomic medicine and screening.
• This method is crucial for establishing genotype-phenotype relationships and understanding disease.
• A framework is proposed to encourage collaborative genomic ascertainment research programs.