Genomic of CONgenital Sideroblastic Anemias (GASCON-2)

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.

Study Overview

• Status: Recruiting
• Conditions: Anemia; Genetics; Erythropoiesis
• Intervention / Treatment: Biological: blood redrawal

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Ophélie Evrard, MD; Phone Number: 33+322835127; Email: evrard.ophelie@chu-amiens.fr

Study Locations

• France
  • Amiens, France, 80054
    • Recruiting
    • Amiens university hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Screening
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Congenital sideroblastic anemia	Biological: blood redrawal; Peripheral blood mononuclear cells collected in EDTA (7 mL) and ACD tube (7 mL) during a routine sample collection for patients
Active Comparator: Patients without Congenital sideroblastic anemia	Biological: blood redrawal; Peripheral blood mononuclear cells collected in EDTA (7 mL) and ACD tube (7 mL) during a routine sample collection for patients

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identification of genetic variants in Congenital sideroblastic anemias	Variants potentially altering the splicing site	1 year
Identification of nonsense and missense genetic variants in Congenital sideroblastic anemias	Nonsense and missense variants: study of protein expression or protein size by Western Blot or protein-protein interactions in blood mononuclear cells	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
level of mitochondrial membrane potential	Measurement of the level of mitochondrial membrane potential (TMRM in flow cytometry)	1 year
Measurement of mitochondrial Ros production	Measurement of mitochondrial Ros production (Mitosox in flow cytometry)	1 year
Measurement of mitochondrial mass	Measurement of mitochondrial mass (MitoTracker in flow cytometry)	1 year
Measurement of erythroid differentiation	Measurement of erythroid differentiation	1 year

Collaborators and Investigators

• Sponsor: Centre Hospitalier Universitaire, Amiens

Study record dates

Study Major Dates

• Study Start (Actual): October 28, 2025
• Primary Completion (Estimated): November 1, 2026
• Study Completion (Estimated): November 1, 2026

Study Registration Dates

• First Submitted: November 17, 2025
• First Submitted That Met QC Criteria: March 3, 2026
• First Posted (Actual): March 10, 2026

Study Record Updates

• Last Update Posted (Actual): March 11, 2026
• Last Update Submitted That Met QC Criteria: March 9, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: genetics; Anemia; erythropoiesis
• Additional Relevant MeSH Terms: Hematologic Diseases; Hemic and Lymphatic Diseases; Anemia
• Other Study ID Numbers: PI2025_843_0155

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No