Targeted mutation screening of 292 candidate genes in 38 children with inborn haematological cytopenias efficiently identifies novel disease-causing mutations

Abstract

Establishing a precise diagnosis is essential in inborn haematological cytopenias to enable appropriate treatment decisions and avoid secondary organ damage. However, both diversity and phenotypic overlap of distinct disease entities may make the identification of underlying genetic aetiologies by classical Sanger sequencing challenging. Instead of exome sequencing, we established a systematic next generation sequencing-based panel targeting 292 candidate genes and screened 38 consecutive patients for disease-associated mutations. Efficient identification of the underlying genetic cause in 17 patients (44·7%), including 13 novel mutations, demonstrates that this approach is time- and cost-efficient, enabling optimal management and genetic counselling.

Keywords: clinical haematology; genetic disorders; immunodeficiency; paediatric haematology.

Figure 1

Targeted NGS‐based panel screen for efficient identification of genetic causes in inherited haematological diseases. (A) A total of 38 patients with molecularly undefined cytopenias were included in the study, and a disease‐causing mutation was identified in 17 (44·7%). (B) May‐Grünwald‐Giemsa stained peripheral blood smear showing characteristic dessicytes and a few target cells in Patient 8 with hereditary xerocytosis caused by (C) a novel mutation in PIEZO1 (NM_001142864.2:c.4082A>G p.Q1361R). In Patient 9, who exhibited characteristic light microscopy findings in (D) peripheral blood, i.e., gross anisocytosis, poikilocytosis and (E) bone marrow, such as erythroid hyperplasia and chromatin bridges between nuclei of two separate erythroblasts, we identified (F) novel compound heterozygous variants (NM_138477.2:c.2044C>T p.R682X and NM_138477.2:c.3575T>C p.L1192S) in codanin 1 (CDAN1) causing congenital dyserythropoietic anaemia type 1. In an infant (Patient 13) with thrombocytopenia and giant platelets (G) [giant platelet (right) and eosinophilic granulocyte (left)], we identified a (H) known causative mutation in MHY9 (NM_002473.4:c.287C>T p.S96L) causing MYH9‐related disease. NGS, next generation sequencing.