TMPRSS6 NON-CODING VARIANTS IN IRIDA PHENOTYPE EXPRESSION IN MONOALLELIC AFFECTED INDIVIDUALS

Vera HOVING¹, Albertine DONKER⁴, Roel SMEETS⁵, Bert VAN DEN HEUVEL⁵, Saskia SCHOLS¹, Dorine SWINKELS^2,3

¹Department of Hematology, Radboud university medical center, Nijmegen, Netherlands
²Radboud Laboratory for Diagnostics, Department of Laboratory Medicine, Radboud university medical center, Nijmegen, Netherlands
³Sanquin Blood Bank, Amsterdam, Netherlands
⁴Department of Paediatrics, Maxima Medical Center, Veldhoven, Netherlands
⁵Department of Human Genetics, Radboud university medical center, Nijmegen, Netherlands

Iron refractory iron deficiency anemia (IRIDA), a rare inherited disorder, arises from pathogenic variants in the TMPRSS6-gene. It presents as microcytic anemia with low serum iron concentration and inappropriately high hepcidin levels. Although generally considered an autosomal recessive disorder, some patients express the phenotype with a monoallelic pathogenic exonic TMPRSS6-variant. The underlying pathophysiology in these patients remains unknown, causing diagnostic uncertainty.

This retrospective monocenter study explored non-coding variants as potential contributors to the IRIDA-phenotype through full-sequencing of TMPRSS6. Symptomatic carriers (monoallelic IRIDA-genotype with phenotype), asymptomatic carriers (monoallelic IRIDA-genotype without phenotype expression) and wild-type relatives (no TMPRSS6 variant, no phenotype) were included. Whole-exome sequencing of iron-regulating genes was performed to exclude polygenic inheritance. Data were analyzed at family level and at individual level for subjects with and without included relatives, respectively. Variants were considered contributors if they were i) deemed potentially pathogenic based on in silico tools, and for those found in families ii) inherited in trans.

Polygenic inheritance was excluded. Full-sequencing of TMPRSS6 in 27 subjects revealed 224 non-coding variants. Familial segregation analysis of these variants identified 13 trans-inherited variants, including one potentially pathogenic according to in silico tools. Individual-level analysis revealed that 21 of these 224 were found exclusively in symptomatic carriers without included relatives, with three potentially affecting splice sites and one located in the predicted promoter region. No variant was found exclusively in symptomatic carriers.

Full-sequencing of TMPRSS6 revealed non-coding variants potentially influencing phenotypic expression. Further functional studies are warranted to confirm their implications for patient care.