CoGenesis® Haematological

CoGenesis® Haematological is a targeted next-generation sequencing (NGS) panel covering 270 genes across four disease categories of rare hereditary blood disorders. It is designed to identify the underlying genetic cause in patients with unexplained anaemia, abnormal blood counts, bone marrow failure, or a family history of haematological disease.

Blood disorders can arise from defects in red blood cells — affecting their haemoglobin, membrane integrity, or enzyme function — from failure of the bone marrow to produce adequate blood cells, from platelet abnormalities affecting clotting and bleeding, or from inherited predisposition to haematological cancers. Because many of these conditions share overlapping clinical features, molecular genetic testing is often essential to reach a precise diagnosis and direct appropriate management.

Red cell disorders: The panel covers three main mechanisms. Haemoglobinopathies — including alpha-thalassaemia, beta-thalassaemia, and sickle cell disease — result from mutations in the globin genes (HBA1, HBA2, HBB, HBD, HBG1, HBG2). Red cell enzyme deficiencies (including G6PD, PKLR, GPI, BPGM, TPI1, GCLC, GSR, GSS, and others) impair the cell's capacity to withstand oxidative or metabolic stress, causing haemolytic anaemia. Red cell membrane disorders (ANK1, EPB41, EPB42, SPTA1, SPTB, RHAG) disrupt the structural integrity of the erythrocyte, leading to hereditary spherocytosis, elliptocytosis, or stomatocytosis.

Bone marrow failure syndromes: The panel comprehensively covers inherited aplastic anaemia and marrow failure conditions. Fanconi anaemia — caused by biallelic mutations in any of fifteen FANC pathway genes — is associated with progressive bone marrow failure, physical anomalies, and marked predisposition to AML and solid tumours. Diamond-Blackfan anaemia results from haploinsufficiency of ribosomal protein genes (multiple RPL and RPS family members). Dyskeratosis congenita — involving DKC1, TERC, TERT, TINF2, RTEL1, NHP2, NOP10, and WRAP53 — causes bone marrow failure through progressive telomere shortening. Shwachman-Diamond syndrome (SBDS, DNAJC21) and congenital neutropenia (ELANE, HAX1, G6PC3) are also included.

Platelet disorders: The panel covers inherited thrombocytopenias — including MYH9-related macrothrombocytopenia, ANKRD26-related and RUNX1-related familial thrombocytopenia — as well as qualitative platelet defects (ITGA2B/ITGB3 causing Glanzmann thrombasthenia; GP6) and Wiskott-Aldrich syndrome (WAS, WIPF1). These span a clinical spectrum from mild bruising to life-threatening haemorrhage.

Myeloid predisposition and inflammatory haematological disorders: Germline variants in RUNX1, GATA2, CEBPA, and SAMD9/SAMD9L confer inherited predisposition to myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). The panel also covers genes relevant to myeloproliferative neoplasms (JAK2, CALR, MPL) and autoinflammatory disorders with haematological manifestations — including familial Mediterranean fever (MEFV), cryopyrin-associated periodic syndromes (NLRP3), and STING-associated vasculopathy (TMEM173).

A confirmed molecular diagnosis has direct clinical implications: it guides disease-specific management, informs surveillance for secondary malignancies, determines eligibility for haematopoietic stem cell transplantation, supports family counselling and cascade testing, and in selected cases may direct targeted therapy.

1. Patients with unexplained chronic or episodic haemolytic anaemia in whom red cell morphology and standard biochemical testing have not identified the underlying cause — encompassing membrane disorders (hereditary spherocytosis, elliptocytosis), enzymopathies (G6PD deficiency, pyruvate kinase deficiency), and haemoglobinopathies beyond those detectable by HPLC.

2. Children or adults with hypoplastic or aplastic anaemia, cytopenias, or pancytopenia in whom an inherited bone marrow failure syndrome is suspected — including Fanconi anaemia, Diamond-Blackfan anaemia, dyskeratosis congenita, or Shwachman-Diamond syndrome — where molecular confirmation is required to guide clinical management, cancer surveillance, and transplant planning.

3. Individuals with inherited thrombocytopenia or qualitative platelet disorders — including macrothrombocytopenia (MYH9-related), familial thrombocytopenia (ANKRD26, RUNX1), Glanzmann thrombasthenia (ITGA2B/ITGB3), or Wiskott-Aldrich syndrome — where a genetic diagnosis will direct clinical management, bleeding precautions, and recurrence risk counselling.

4. Patients or families with germline predisposition to myelodysplastic syndrome or acute myeloid leukaemia — particularly those with early-onset MDS/AML, familial clustering, or clinical features suggesting GATA2 deficiency, RUNX1 familial platelet disorder, or SAMD9/SAMD9L-related monosomy 7 syndrome — where identification of the causal variant enables cascade family testing and surveillance planning.

5. Patients with recurrent or atypical autoinflammatory features alongside cytopenias or splenomegaly, in whom a primary haematological inflammatory disorder (MEFV/familial Mediterranean fever, NLRP3/cryopyrin-associated periodic syndromes, or TMEM173/STING-associated vasculopathy) is suspected as the underlying mechanism.

4 sub-panels included:

4mL Peripheral blood (EDTA), 2mL saliva, or buccal swab

Preferred sample type:

• 4mL Blood (EDTA tube),
• Codex-provided buccal swabs (4 swabs)
• Codex-provided saliva collection kit (2mL)

Saliva or buccal swab sample collection: Follow the enclosed instructions; do not eat, drink, or smoke for 30 minutes before collection.

• Results may identify pathogenic, likely pathogenic, or variants of uncertain significance (VUS).
• Positive findings can inform risk‑reducing strategies and treatment options.
• Genetic counseling is recommended to help families understand implications.

Hereditary haematological disorders represent one of the broadest and most clinically heterogeneous categories in medical genetics, encompassing diseases of red cell structure and metabolism, haematopoietic stem cell maintenance, platelet number and function, and germline predisposition to haematological malignancy.

Red cell disorders are among the most prevalent monogenic diseases globally. Haemoglobinopathies — alpha-thalassaemia, beta-thalassaemia, and sickle cell disease — affect an estimated 7% of the world population as carriers, with over 300,000 severely affected births annually. Glucose-6-phosphate dehydrogenase (G6PD) deficiency, the most common red cell enzymopathy, affects approximately 400 million individuals worldwide, presenting with episodic haemolysis triggered by oxidative stress. Pyruvate kinase (PKLR) deficiency and hereditary spherocytosis (ANK1, SPTA1, SPTB, EPB42) are the leading causes of non-immune haemolytic anaemia in northern European populations. Molecular diagnosis is essential for precise subclassification, severity prediction, and family counselling.

Inherited bone marrow failure syndromes (IBMFS) are individually rare but collectively constitute a significant diagnostic category. Fanconi anaemia (FA), with an incidence of approximately 1 in 130,000 births, is caused by biallelic mutations in any of fifteen FANC pathway genes. Clinical urgency is driven by high lifetime cancer risk: cumulative AML/MDS risk exceeds 50%, and head and neck squamous cell carcinoma risk is elevated over 500-fold compared to the general population. Precise genetic subtyping determines complementation group and informs transplant approach. Diamond-Blackfan anaemia (DBA), caused by haploinsufficiency of ribosomal protein genes (RPL and RPS families), has an incidence of approximately 5–7 per million live births. Dyskeratosis congenita — with its hallmark triad of nail dystrophy, reticular skin pigmentation, and oral leukoplakia — carries a 40% cumulative risk of bone marrow failure by age 40 and is caused by germline defects in telomere maintenance genes (DKC1, TERC, TERT, TINF2, RTEL1, NHP2, NOP10, WRAP53).

Germline predisposition to myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML) is increasingly recognised as a distinct clinical entity. RUNX1 familial platelet disorder with myeloid malignancy predisposition, GATA2 deficiency syndrome, CEBPA-related familial AML, and SAMD9/SAMD9L-associated monosomy 7 syndrome are the best-characterised subtypes. The WHO 2022 classification of haematopoietic tumours now formally includes "myeloid neoplasms with germline predisposition", underscoring the clinical importance of germline testing. Early identification enables cascade family testing, surveillance planning, and stem cell transplant donor selection (excluding affected family members).

Platelet disorders span from mild autosomal dominant thrombocytopenias (MYH9-related disease, ANKRD26-related thrombocytopenia) to severe bleeding disorders (Glanzmann thrombasthenia: ITGA2B/ITGB3) and immunodeficiency-associated conditions (Wiskott-Aldrich syndrome: WAS). Molecular diagnosis is critical for differentiating immune thrombocytopenic purpura (ITP) from inherited thrombocytopenia (avoiding unnecessary immunosuppression), determining transplant eligibility, and accurate pre-pregnancy counselling.

Autoinflammatory haematological disorders — including familial Mediterranean fever (MEFV), cryopyrin-associated periodic syndromes (NLRP3), and STING-associated vasculopathy with onset in infancy (TMEM173) — present with cytopenias and systemic inflammation, often mimicking primary haematological disease. Recognition of the genetic basis permits targeted anti-inflammatory therapy (IL-1 inhibitors, JAK inhibitors) rather than haematological treatment. CoGenesis® Haematological consolidates this broad diagnostic landscape into a single comprehensive NGS panel, enabling efficient molecular diagnosis across the full hereditary haematological disease spectrum.