# TMPRSS6 Non-Coding Variants in the Expression of Iron Refractory Iron Deficiency Anemia in Monoallelic Subjects

## TL;DR

This study explores how non-coding genetic changes in the TMPRSS6 gene may cause anemia in people with only one faulty gene copy.

## Contribution

Identifies candidate non-coding variants in TMPRSS6 that may explain monoallelic IRIDA expression.

## Key findings

- 219 non-coding variants were identified, with 31 found only in symptomatic individuals.
- Four specific non-coding variants are proposed as potential contributors to monoallelic IRIDA.
- No evidence of polygenic inheritance from other iron-regulating genes was found.

## Abstract

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.