Genomic of CONgenital Sideroblastic Anemias

Overview

Congenital sideroblastic anemias (CSA) are a group of rare disorders characterized by abnormal iron utilization during erythropoiesis, leading to mitochondrial iron overload, the formation of ring sideroblasts, and ineffective erythropoiesis resulting in anemia. Ring sideroblasts are erythroid precursors that contain non-heme iron deposits in their mitochondria, forming a distinctive ring-like pattern around the nucleus. Mitochondria are double membrane organelle provide a large amount of energy for cellular activities, by the process of oxidative phosphorylation (OXPHOS). The role of mitochondria has been well described in erythropoiesis. CSA exhibits clinical heterogeneity, affecting only the erythroid system in some cases, while in others presenting as part of broader syndromic conditions. Their molecular basis remains imperfectly known, although the development of next- generation sequencing technology brought tremendous advances in the understanding of their genetic features. More than 20 genes have been identified as causative of CSA, with all modes of inheritance observed: X-linked recessive, autosomal dominant, autosomal recessive, pseudo- dominant, and mitochondrial. These genes are typically involved in one of four key mitochondrial pathways: i) Heme biosynthesis (e.g., ALAS2, SLC25A38); ii) Iron-sulfur cluster biosynthesis and transport (e.g., GLRX5, HSPA9, HSCB); iii) tRNA synthesis and maturation (e.g., PUS1, YARS2, LARS2, IARS2, SARS2, MARS1, TRNT1); iv) Mitochondrial respiratory chain synthesis (e.g., NDUFB11). However, in nearly 30% of cases within the French CSA cohort, the underlying genetic cause remains unknown. In these patients with molecularly unexplained whole genome or exome sequencing approaches focusing on genes involved in mitochondrial function and iron metabolism identified several possibly pathogenic variants in CSA patients. These genes were not clearly described as playing a role in erythropoiesis or heme or iron metabolism. We hope to confirm their role in CSA. However, in nearly 30% of cases within the French CSA cohort , the underlying genetic cause remains unknown. The investigators hope to confirm the role in CSA of gene identified with exome sequencing approaches.

Interventions

• Biological blood redrawal
  Peripheral blood mononuclear cells collected in EDTA (7 mL) and ACD tube (7 mL) during a routine sample collection for patients

Primary outcome measures

• Identification of genetic variants in Congenital sideroblastic anemias [Time frame: 1 year]
• Identification of nonsense and missense genetic variants in Congenital sideroblastic anemias [Time frame: 1 year]

Secondary outcome measures (4)

• level of mitochondrial membrane potential [Time frame: 1 year]
• Measurement of mitochondrial Ros production [Time frame: 1 year]
• Measurement of mitochondrial mass [Time frame: 1 year]
• Measurement of erythroid differentiation [Time frame: 1 year]

Eligibility criteria

Inclusion criteria

• Patient with unexplained congenital sideroblastic anemia on the molecular side with the gene panels used routinely
• Patients already identified by exome sequencing approach carrying bi-allelic variants of candidate genes of the mitochondrial respiratory pathway.
• Patients meeting the same criteria who will be identified prospectively over the next 12 months

Exclusion criteria

• NA

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Screening

Study locations

France · 1 center

• Amiens University Hospital — Amiens

Identifiers

NCT: NCT07459816 · PI2025_843_0155

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗