Severe congenital neutropenia (CN) is a pre-leukemia bone marrow failure syndrome presented with profound neutropenia early after birth due to markedly diminished granulocytic differentiation of bone marrow hematopoietic stem and progenitor cells (HSPCs). G-CSF is the first-choice therapy in CN patients (Bonilla et al. 1989; Dale et al. 1993).
With the advent of next generation sequencing, the discovery of causative genetic variants of human inherited diseases has rapidly accelerated. As a result, germline mutations in more than 25 genes were identified to be associated with CN (Skokowa et al. 2017). Based on the data from the Severe Congenital Neutropenia International Registry (SCNIR) database, mutations in ELANE is responsible for the majority of CN cases (n=139, 26,6%) (Figure 1), whereas the second biggest group (n=123, 23,5%) after ELANE-CN cohort comprises unclassified cases, where a genetic diagnosis could not be established so far
Precise genetic diagnosis in patients with genetically unclassified severe congenital neutropenia enables improved therapeutic surveillance and better patient management by clinicians.
Figure 1. Distribution of CN patients in the SCNIR database according to their genetic diagnosis (status on 10/2019).
The results of exome sequencing/trio analysis will be ready in 3 months. In the case of identification of novel candidate mutations/genes the collaboration can be extended to generation of patient iPSCs followed by CRISPR/Cas9 correction of candidate variant and/or variant pathogenicity evaluation in a zebrafish model.
Participation in the initiative is open for all members of the Young EuNET-INNOCHRON
For the enrollment of patients in the study and before sample submission please contact Maksim Klimiankou, PhD Maksim.Klimiankou@med.uni-tuebingen.de.
For question regarding the clinical diagnosis of neutropenia please contact Prof. Dr. Julia Skokowa, Julia.Skokowa@med.uni-tuebingen.de
Inclusion and exclusion criteria for patients in the study
Signed “Informed consent form for adult patients or minor patients' parents (legal Guardian)” is required (the form can be found at https://severe-chronic-neutropenia.org/en/forms).
It is recommended that patient(-s) are registered in the Severe Chronic Neutropenia International Registry using “Registration Form” (the form can be found at https://severe-chronic-neutropenia.org/en/forms).
Samples should be sent to
Maksim Klimiankou, PhD
Division of Translational Oncology
Department of Oncology, Hematology, Clinical Immunology and Rheumatology
University Hospital Tübingen
Otfried-Müller Str. 10
Figure 2. Project workflow.