Guidelines for genetic studies in single patients: lessons from primary immunodeficiencies

Area of Science:

• Genetics
• Immunology
• Human Physiology

Background:

• Primary immunodeficiencies (PIDs) are often monogenic, with a significant portion initially identified in single patients.
• Establishing genotype-phenotype causality in single cases is challenging but crucial for understanding disease mechanisms.

Discussion:

• Next-generation sequencing (NGS), iPSC technology, and CRISPR/Cas9 facilitate genetic discovery in single patients.
• Validation requires demonstrating that the candidate genotype is absent in healthy individuals and functionally impacts the gene product.
• Confirmation through cellular or animal models is essential for establishing a causal link.

Key Insights:

• 21% of monogenic PID etiologies were first reported in single patients.
• Three criteria are proposed to validate genotype-phenotype causality from single-case studies.
• Single-patient studies, when rigorously validated, are valuable for discovering Mendelian disorders.

Outlook:

• Encouraging single-patient case reports can accelerate the understanding of rare diseases.
• This approach can uncover critical pathways in both physiological and pathological processes.
• Further application of advanced genetic technologies in single cases holds promise for broader medical fields.