Digenic mutations in severe congenital neutropenia

Germeshausen, Manuela; Zeidler, Cornelia; Stuhrmann, Manfred; Lanciotti, Marina; Ballmaier, Matthias; Welte, Karl

doi:10.3324/haematol.2009.017665

Cited by 52 publications

(43 citation statements)

References 26 publications

(34 reference statements)

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“…The dual contribution of the type I and type II IFNs to susceptibility to viral infection is illustrated by the IFNAR/IFNGR double-knockout mice, which are more susceptible The unbiased approach inherent in next-generation sequencing has shown that approximately 5% of sequenced patients have disease-causing multiloci variants (14). Multigenic mutations have been shown to shape the phenotype of patients with autoimmunity, severe congenital neutropenia, and familial HLH (15)(16)(17). This is the first report, to our knowledge, of a digenic human primary immunodeficiency caused by defects specific to IFNAR1 and IFN-GR2.…”

Section: C266fsmentioning

confidence: 99%

A digenic human immunodeficiency characterized by IFNAR1 and IFNGR2 mutations

Hoyos-Bachiloglu¹,

Chou²,

Sodroski³

et al. 2017

Journal of Clinical Investigation

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Section: C266fsmentioning

confidence: 99%

A digenic human immunodeficiency characterized by IFNAR1 and IFNGR2 mutations

Hoyos-Bachiloglu¹,

Chou²,

Sodroski³

et al. 2017

Journal of Clinical Investigation

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“…Activating mutations in the WAS gene have been found to be responsible for some cases of X-linked-SNC [54,55] (EO, IV, V, 8.1, B). Finally as patients with digenic mutations have been found [56], mutation search in a second gene known to be involved in SCN should also be considered. In case these investigations fail to detect a genetic cause of SCN, the panel recommended to carefully re-evaluate history, clinical symptoms and specific laboratory tests.…”

Section: (Eo 9 A)mentioning

confidence: 99%

Congenital and acquired neutropenia consensus guidelines on diagnosis from the Neutropenia Committee of the Marrow Failure Syndrome Group of the AIEOP (Associazione Italiana Emato‐Oncologia Pediatrica)

Fioredda

Calvillo

Bonanomi

et al. 2011

Pediatric Blood & Cancer

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Congenital and acquired neutropenia are rare disorders whose frequency in pediatric age may be underestimated due to remarkable differences in definition or misdiagnosed because of the lack of common practice guidelines. Neutropenia Committee of the Marrow Failure Syndrome Group (MFSG) of the AIEOP (Associazione Italiana Emato‐Oncologia Pediatrica) elaborated this document following design and methodology formerly approved by the AIEOP board. The panel of experts reviewed the literature on the topic and participated in a conference producing a document which includes a classification of neutropenia and a comprehensive guideline on diagnosis of neutropenia. Pediatr Blood Cancer 2011;57:10–17. © 2011 Wiley‐Liss, Inc.

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“…This could explain the unexpected occurrence of di-genic mutations (ELANE and HAX1) in a single SCN patient and the presence of an ELANE mutation in a patient from one of the Kostmann families, who had unaffected HAX1 genes. 11,13 These phenomena are unlikely to happen by chance, given the rarity of ELANE and HAX1 mutations in the healthy population. Similarly, host factors may have influenced the course of the disease in the two patients reported by Rolf Kostmann, who had significantly milder symptoms than others within the same pedigree.…”

Section: Scn With Mutations In Hax1 (Hax1-scn)mentioning

confidence: 99%

Game of clones: the genomic evolution of severe congenital neutropenia

Touw

2015

Hematology

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Severe congenital neutropenia (SCN) is a genetically heterogeneous condition of bone marrow failure usually diagnosed in early childhood and characterized by a chronic and severe shortage of neutrophils. It is now well-established that mutations in HAX1 and ELANE (and more rarely in other genes) are the genetic cause of SCN. In contrast, it has remained unclear how these mutations affect neutrophil development. Innovative models based on induced pluripotent stem cell technology are being explored to address this issue. These days, most SCN patients receive life-long treatment with granulocyte colony-stimulating factor (G-CSF, CSF3). CSF3 therapy has greatly improved the life expectancy of SCN patients, but also unveiled a high frequency of progression toward myelodysplastic syndrome (MDS) and therapy refractory acute myeloid leukemia (AML). Expansion of hematopoietic clones with acquired mutations in the gene encoding the G-CSF receptor (CSF3R) is regularly seen in SCN patients and AML usually descends from one of these CSF3R mutant clones. These findings raised the questions how CSF3R mutations affect CSF3 responses of myeloid progenitors, how they contribute to the pre-leukemic state of SCN, and which additional events are responsible for progression to leukemia. The vast (sub)clonal heterogeneity of AML and the presence of AML-associated mutations in normally aged hematopoietic clones make it often difficult to determine which mutations are responsible for the leukemic process. Leukemia predisposition syndromes such as SCN are unique disease models to identify the sequential acquisition of these mutations and to interrogate how they contribute to clonal selection and leukemic evolution. Learning Objectives• Knowledge of the possible mechanisms by which mutations in ELANE or HAX1 cause SCN and the controversies that preclude a unifying hypothesis • Understanding of how somatic mutations in CSF3R affect CSF3-induced signal transduction and contribute to the expansion of hematopoietic clones in SCN

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Digenic mutations in severe congenital neutropenia

Cited by 52 publications

References 26 publications

A digenic human immunodeficiency characterized by IFNAR1 and IFNGR2 mutations

A digenic human immunodeficiency characterized by IFNAR1 and IFNGR2 mutations

Congenital and acquired neutropenia consensus guidelines on diagnosis from the Neutropenia Committee of the Marrow Failure Syndrome Group of the AIEOP (Associazione Italiana Emato‐Oncologia Pediatrica)

Game of clones: the genomic evolution of severe congenital neutropenia

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