Probable digenic inheritance of Diamond–Blackfan anemia

Abstract

A 26‐year‐old female proband with a clinical diagnosis and consistent phenotype of Diamond–Blackfan anemia (DBA, OMIM 105650) without an identified genotype was referred to the Undiagnosed Diseases Network. DBA is classically associated with monoallelic variants that have an autosomal‐dominant or ‐recessive mode of inheritance. Intriguingly, her case was solved by a detection of a digenic interaction between non‐allelic RPS19 and RPL27 variants. This was confirmed with a machine learning structural model, co‐segregation analysis, and RNA sequencing. This is the first report of DBA caused by a digenic effect of two non‐allelic variants demonstrated by machine learning structural model. This case suggests that atypical phenotypic presentations of DBA may be caused by digenic inheritance in some individuals. We also conclude that a machine learning structural model can be useful in detecting digenic models of possible interactions between products encoded by alleles of different genes inherited from non‐affected carrier parents that can result in DBA with an unrealized 25% recurrence risk.