Probable digenic inheritance of Diamond-Blackfan anemia.

Area of Science:

• Genetics
• Hematology
• Computational Biology

Background:

• Diamond-Blackfan anemia (DBA) is a rare genetic disorder characterized by bone marrow failure.
• DBA is classically linked to monoallelic variants in ribosomal protein genes, exhibiting autosomal dominant or recessive inheritance patterns.

Observation:

• A 26-year-old female with a Diamond-Blackfan anemia phenotype lacked an identified genotype through standard genetic analysis.
• Referral to the Undiagnosed Diseases Network led to the investigation of a complex genetic interaction.

Findings:

• Digenic inheritance involving non-allelic variants in RPS19 and RPL27 was identified as the cause of DBA in this proband.
• Machine learning structural modeling, co-segregation analysis, and RNA sequencing confirmed the digenic interaction.
• This represents the first report of DBA caused by digenic variants in non-allelic genes, validated by a machine learning structural model.

Implications:

• Atypical DBA presentations may arise from digenic inheritance, expanding the known genetic mechanisms of the disorder.
• Machine learning models can detect digenic interactions between variants in different genes, revealing complex inheritance patterns.
• This finding highlights a potential 25% recurrence risk in families with non-affected carrier parents due to digenic inheritance.