Genomics of iron refractory iron deficiency anemia phenotype reveals a spectrum of novel pathogenic biallelic and monoallelic TMPRSS6 variants and rare overlapping disorders

Sharma, Pankaj; Bhatia, Prateek; Singh, Minu; Das, Reena; Attri, Savita Verma; Ghara, Niharendu; Prasada, L. Harsha; Trehan, Amita

doi:10.1016/j.gene.2023.147981

Gene

2024

DOI: 10.1016/j.gene.2023.147981

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Genomics of iron refractory iron deficiency anemia phenotype reveals a spectrum of novel pathogenic biallelic and monoallelic TMPRSS6 variants and rare overlapping disorders

Pankaj Sharma,

Prateek Bhatia,

Minu Singh

et al.

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Novel TMPRSS6 variants and their impact on iron‐refractory iron deficiency anaemia in pregnancy: A North Indian genotype phenotype study

Sharma,

Kumar,

Rawat

et al. 2024

Br J Haematol

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SummaryIron‐refractory iron deficiency anaemia (IRIDA) is a rare autosomal recessive disorder, distinguished by hypochromic microcytic anaemia, low transferrin levels and inappropriately elevated hepcidin (HEPC) levels. It is caused by mutations in TMPRSS6 gene. Systematic screening of 500 pregnant women with iron deficiency anaemia having moderate to severe microcytosis with no other causes of anaemia were enrolled to rule out oral iron refractoriness. It identified a final cohort of 10 (2.15% prevalence) individuals with IRIDA phenotype. Haematological and biochemical analysis revealed significant differences between iron responders and iron non‐responders, with iron non‐responders showing lower haemoglobin, red blood cell count, serum iron and serum ferritin levels, along with elevated HEPC (9.47 ± 2.75 ng/mL, p = 0.0009) and erythropoietin (4.58 ± 4.07 µ/mL, p = 0.0196) levels. Genetic sequencing of the TMPRSS6 gene in this final cohort identified 10 novel variants, including seven missense and three frame‐shift mutations, with four missense variants showing high functional impact defining the IRIDA phenotype. Structural analysis revealed significant damage caused by two variants (p.L83R and p.S235R). This study provides valuable insights into IRIDA among pregnant women in the Indian subcontinent, unveiling its underlying causes of unresponsiveness, genetic mechanisms and prevalence. Furthermore, research collaboration is essential to validate these findings and develop effective treatments.

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Novel TMPRSS6 variants and their impact on iron‐refractory iron deficiency anaemia in pregnancy: A North Indian genotype phenotype study

Sharma,

Kumar,

Rawat

et al. 2024

Br J Haematol

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show abstract

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Genomics of iron refractory iron deficiency anemia phenotype reveals a spectrum of novel pathogenic biallelic and monoallelic TMPRSS6 variants and rare overlapping disorders

Cited by 1 publication

References 9 publications

Novel TMPRSS6 variants and their impact on iron‐refractory iron deficiency anaemia in pregnancy: A North Indian genotype phenotype study

Novel TMPRSS6 variants and their impact on iron‐refractory iron deficiency anaemia in pregnancy: A North Indian genotype phenotype study

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