Interpreting variants in genes affected by clonal hematopoiesis in population data

Area of Science:

• Genomics
• Human Genetics
• Computational Biology

Background:

• Population databases like gnomAD are crucial for human genome interpretation.
• Variant frequencies and depletion scores are fundamental for assessing variant-gene-disease links.
• Clonal hematopoiesis (CH) introduces somatic variants that can confound these analyses.

Purpose of the Study:

• To provide insights into interpreting population variant data in genes affected by CH.
• To offer recommendations for the careful review of 36 CH genes associated with neurodevelopmental conditions.
• To address the challenge of distinguishing somatic CH variants from pathogenic germline variants.

Main Methods:

• Analysis of population variant frequency data.
• Evaluation of depletion scores in the context of CH.
• Review of established CH genes and their association with Mendelian conditions.

Main Results:

• Somatic variants in CH can significantly alter variant frequencies and depletion scores.
• Default filtering based on population data may incorrectly exclude genuine germline variants.
• Specific CH genes are associated with neurodevelopmental disorders, requiring careful interpretation.

Conclusions:

• Interpreting population variant data in CH-affected genes requires specialized approaches.
• Recommendations are provided for the accurate assessment of variants in 36 CH genes linked to neurodevelopmental conditions.
• Distinguishing somatic CH variants from pathogenic germline variants is critical for accurate genetic diagnosis.