Furuta Yutaka, Tinker Rory J, Gulsevin Alican, Neumann Serena M, Hamid Rizwan, Cogan Joy D, Rives Lynette, Liu Qi, Chen Hua-Chang, Joos Karen M, Phillips John A
Department of Pediatrics, Division of Medical Genetics and Genomic Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Department of Chemistry, Center for Structural Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Am J Med Genet A. 2024 Mar;194(3):e63454. doi: 10.1002/ajmg.a.63454. Epub 2023 Oct 27.
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.
一名26岁的女性先证者，临床诊断为钻石黑范贫血（DBA，OMIM 105650）且具有一致的表型，但未鉴定出基因型，被转诊至未确诊疾病网络。DBA通常与具有常染色体显性或隐性遗传模式的单等位基因变异相关。有趣的是，通过检测非等位基因RPS19和RPL27变异之间的双基因相互作用解决了她的病例。这通过机器学习结构模型、共分离分析和RNA测序得到了证实。这是第一份由机器学习结构模型证明的两个非等位基因变异的双基因效应导致DBA的报告。该病例表明，DBA的非典型表型表现可能在某些个体中由双基因遗传引起。我们还得出结论，机器学习结构模型可用于检测由未受影响的携带者父母遗传的不同基因等位基因编码的产物之间可能相互作用的双基因模型，这些相互作用可能导致DBA，且复发风险未实现25%。
