Curable Hereditary Anemias in Children

Across many low and middle income countries, thousands of children are born every year with hereditary hemolytic anemias that are, in principle, curable. For a growing number of these disorders, modern bone marrow transplantation and emerging gene therapies can restore near normal life expectancy. In high incomecountries, large registries and coordinated programs have already shown that cure is possible for many patients.

In practice, most children in under resourced settings never reach curative treatment. They are underdiagnosed, managed only with transfusions, and die young from organ failure, treatment complications, or cancer.

This project builds an international pediatric cohort for hereditary anemias, starting with a uniquely informative population in Central Asia and designed from the beginning to be expanded to other regions with similar risks. We will combine careful clinical characterization and modern genetic testing to map thereal burden of these diseases, adapt successful risk stratification approaches from existing registries, and prepare the ground for curative programs where they are needed most.

Problem

Countries that historically lay in malaria zones and have high rates of marriage within extended families often carry an unusually high burden of hereditary hemolyticanemias in children, including Fanconi anemia, beta thalassemia, and other rare congenital anemias.

For many of these conditions, curative options already exist. With timely bone marrow transplantation or modern gene therapy, treated children can achieve qualityand length of life comparable to their healthy peers. Without curative treatment, most do not live beyond their second or third decade. Many die in childhood, either because they do not receive regular, safe transfusions orbecause long term iron overload and organ damage lead to heart failure, liverdisease, infections, or aggressive cancers.

In manycenters today:

- clinical diagnosis is based mainly on symptoms and simple blood tests
- genetic subtypes and rare variants are unknown
- transplant risks and conditioning strategies specific to this population arepoorly understood
- children have access only to supportive transfusion care and, in very rarecases, to curative therapy abroad.

At the same time, several countries are now opening new pediatric hematology and transplant units. These centers face a critical gap: they do not yet know the full clinical and genetic landscape of the children they will be treating, and they are not yet connected to international data networks that could guide their decisions.

Solution

We will create a structured pediatric hereditary anemia cohort with deep clinical and genetic characterization, starting with children in a Central Asian country and then extending the model to other regions with similar risk patterns. The project will:

- identify and enroll children with suspected hereditary hemolytic anemias
- confirm diagnosis through cytogenetic and molecular genetic testing
- systematically document complications, organ damage, and previous treatment histories
- adapt risk stratification and transplant strategies from established international registries to this specific population
- build the clinical and laboratory platform needed for future gene therapy programs.

By turning a fragmented, mostly invisible group of children into a well described, trackable cohort that is compatible with international standards, we make itpossible to move from basic supportive care to deliberate planning of curative treatments.

For achild with a hereditary anemia, the difference between lifelong transfusions and a well planned transplant or gene therapy is the difference between early death and a near normal lifespan.

For families, access to curative options means an end to constant hospital visits, financial and emotional exhaustion, and the fear of losing a child in adolescence or early adulthood.

For health systems, a clear understanding of the true number of affected children, their genetic profiles, and their long term risks is essential to plan:

- how many transplants and advanced treatments will be needed

- what laboratory and imaging infrastructure is required

- which international collaborations for genetherapy and clinical trials should be prioritized

- how to design screening and counseling programs to prevent new severe cases in the future.

For the wider scientific and clinical community, this cohort fills a blind spot. Many hereditary anemia studies and registries focus on European and North American populations or selected regions with strong research infrastructure. Children from Central Asia and other regions with similar ethnogenesis and family structures are underrepresented, even though their risk may be much higher. Including them is not only a question of fairness, but also an opportunity to understand rare variants and outcomes that do not appear in other datasets.

The project is organized in several connected steps.

First, identification and clinical enrollment
We work with pediatric hematology and oncology centers to identify childrenwith suspected hereditary hemolytic anemias. Eligibility is based on persistent anemia, suggestive blood smear and laboratory findings, and family history. Each child and family is counseled, and informed consent is obtained according to international standards.

Second, cytogenetic and molecular testing
Eligible patients undergo:

- cytogenetic stress testing to identify Fanconi anemia and related chromosomal instability syndromes
- whole exome sequencing to detect known and novel variants in genes associated with hereditary anemias
- targeted confirmation of variants where needed.

All results are interpreted in a clinical context, with careful classification of variants and clear feedback to treating physicians and families.

Third, clinical and biomarker assessment
For each child, we collect standardized data on growth, organ function, and complications. This includes:

- history of transfusions and iron chelation
- assessment of iron overload using magnetic resonance imaging of the liver and, when indicated, other organs
- laboratory biomarkers that reflect organ stress and damage.

Fourth, risk adapted transplant strategy
Based on the combined clinical and genetic picture, and drawing on experience from established national and international registries, we work with transplant teams to develop risk adapted conditioning regimens and supportive care plans. The aim is to maximize survival and cure while minimizing transplant relatedmortality and late effects, taking into account the specific risks of thispopulation and the resources of local centers.

Fifth, preparing for gene therapy
By systematically defining the genetic spectrum and clinical course of these disorders in this cohort, we create a natural platform for future participation in gene therapy trials and for local implementation when these therapies become more widely available. The data will help to select appropriate candidates, anticipate risks, and monitor long-term outcomes.

The initial focus is on:

- Fanconi anemia and beta thalassemia in children
- a Central Asian pediatric population with high consanguinity and historical exposure to malaria
- close collaboration between emerging transplant centers, pediatric hematologyunits, and advanced genetic laboratories.

The broader scope is international. The methods, data structures, consent models, and analytical approaches are designed so that:

- other centers in countries with similar risk patterns can join the cohort
- data can be harmonized across regions and compared with existing registries
- future analyses can compare outcomes between different populations and health systems
- the platform can be extended to additional hereditary anemias and related disorders.

For children and families:

- earlier and more accurate diagnosis of hereditary anemias
- access to curative options through locally available bone marrow transplantation programs and, when needed, international referral
- better management of iron overload and other complications
- a realistic perspective on long term survival, family planning, and future risks.

For clinicians and centers:

- clear, practical protocols for diagnostic workup and risk adapted transplant strategies
- a structured registry and dataset that supports both everyday care and research
- stronger justification for investments in transplant and genetic laboratory infrastructure
- connections to international networks working on hereditary anemias, transplantation, and gene therapy.

For health systems and donors:

- reliable data on the true burden of hereditary pediatric anemias in underrepresented regions
- evidence to guide investments in curative programs rather than indefinite supportive care
- a foundation for participation in international gene therapy efforts and multicenter trials.

For science and future therapies:

- discovery and documentation of rare and population specific variants
- data that can be used in future artificial intelligence models for risk prediction and outcome forecasting in hereditary anemias
- a living cohort that can support long term follow up of transplant and genetherapy results across diverse settings.

The project combines:

- standardized clinical data collection using harmonized electronic case report forms
- cytogenetic analysis with stress testing of chromosomes
- whole exome sequencing with expert clinical interpretation
- magnetic resonance imaging protocols for iron overload assessment
- a secure, de identified database that allows pooled analyses across centers while protecting patient privacy.

OncoHelperAI and its partners provide the the complete project office function, including study design support, data standards, analytic frameworks, and coordination between clinical teams in Central Asia, laboratory partners, and international advisors. Overtime, the dataset will be ready for development of artificial intelligence tools that can help predict transplant risks, organ complications, and longterm outcomes for individual children

The immediate next steps include:

- finalizing the study protocol and ethics approvals with the first participating pediatric hematology and transplant centers
- training local teams in standardized enrollment, consent, and data collection
- establishing laboratory pipelines for cytogenetic testing, sequencing, and imaging based assessment of iron overload
- enrolling the first cohort of children and beginning joint case conferences toshape risk adapted transplant plans.

As funding allows, the cohort will expand to additional centers and countries with similar risk profiles, transforming what is now a scattered group of undiagnosed or under treated children into a visible, organized population witha realistic path to cure.

Your support will help us move children with hereditary anemias from lifelong dependence on transfusions and early death to a life that is longer, healthier, and more secure. By donating in this cohort and its infrastructure, you are helping to bring proven curative approaches to regions and families that have so far been left behind, while adding important missing data to the global picture.