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TMPRSS6 Non-Coding Variants in the Expression of Iron Refractory Iron Deficiency Anemia in Monoallelic Subjects
Vera Hoving1,2, Albertine E Donker2,3, Roel J P Smeets4
1Department of Hematology, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands.
Background:
Iron-refractory iron deficiency anemia (IRIDA) is a rare hereditary disorder caused by pathogenic variants in TMPRSS6, characterized by microcytic anemia, low circulating iron levels, and inappropriately high hepcidin levels. Although IRIDA is typically an autosomal recessive disorder, some individuals with a monoallelic pathogenic exonic TMPRSS6 variant exhibit the phenotype, suggesting additional contributing factors. The mechanisms underlying monoallelic IRIDA remain unclear, complicating diagnosis. This study aimed to investigate the potential role of non-coding TMPRSS6 variants and polygenic inheritance in monoallelic IRIDA.
Methods:
We performed full-gene sequencing of TMPRSS6 in a cohort of 27 subjects, including 6 families (7 symptomatic monoallelic, 7 asymptomatic monoallelic, and 4 wild-type subjects) and 9 isolated symptomatic monoallelic subjects. Whole-exome sequencing of other iron-regulating genes was conducted to evaluate polygenic inheritance. Non-coding variants were assessed for inheritance patterns using family segregation analysis, when available, and for pathogenic potential using in silico prediction tools.
Results:
Sequencing identified 219 non-coding variants, of which 31 (14 trans-inherited and 17 with unknown inheritance) were exclusive to symptomatic subjects. Two trans-inherited variants (rs80140288 (c.229+945C>T) and rs146953827 (c.230-938_230-937del)) were predicted to affect splicing, while two additional variants (rs78987624 (c.-7001G>A) and rs117575523 (c.*503C>G)) were located in regulatory regions (with unknown inheritance). Whole-exome sequencing did not support polygenic involving other iron-regulating genes.
Conclusions:
This study highlights four candidate non-coding variants that may contribute to IRIDA expression in monoallelic subjects, offering new insights into its genetic basis. Functional validation is required to confirm their role in disease pathogenesis, refine genotype-phenotype correlations, and improve diagnostic accuracy in monoallelic IRIDA.
Insights
This study identified four non-coding variants in TMPRSS6 that may cause iron-refractory iron deficiency anemia (IRIDA) in individuals with only one affected gene copy. Further research is needed to confirm their role in IRIDA.
Area of Science:
- Genetics
- Hematology
- Molecular Biology
Background:
- Iron-refractory iron deficiency anemia (IRIDA) is a rare genetic disorder linked to TMPRSS6 variants.
- While typically autosomal recessive, some individuals with a single pathogenic TMPRSS6 variant develop IRIDA, indicating other factors are involved.
- The genetic basis of monoallelic IRIDA is not fully understood, complicating diagnosis.
Purpose of the Study:
- To investigate the role of non-coding TMPRSS6 variants in monoallelic IRIDA.
- To explore the potential contribution of polygenic inheritance to the IRIDA phenotype in these cases.
Main Methods:
- Full-gene sequencing of TMPRSS6 was performed on 27 subjects from 6 families and 9 isolated cases.
- Whole-exome sequencing was used to assess for polygenic inheritance involving other iron-regulating genes.
- Non-coding variants were analyzed for inheritance patterns and predicted pathogenicity using in silico tools.
Main Results:
- 219 non-coding variants were identified, with 31 exclusive to symptomatic subjects.
- Four candidate variants, including two predicted to affect splicing and two in regulatory regions, were identified.
- Whole-exome sequencing did not provide evidence for polygenic inheritance involving other iron-regulating genes.
Conclusions:
- Four candidate non-coding TMPRSS6 variants may contribute to the expression of IRIDA in monoallelic subjects.
- These findings offer new insights into the genetic underpinnings of monoallelic IRIDA.
- Functional studies are necessary to validate these variants and improve diagnostic accuracy for IRIDA.
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