Cytopenias and congenital anaemias

Gene: CSF3R

Comment on phenotypes: This entry represents Severe congenital neutropenia (MIM:617014), caused by variants of CSF3R that are inherited in an autosomal recessive manner. In PMID: 24753537 Triot et al identifies a subtype of Severe congenital neutropenia, characterized by recessively inherited, loss-of-function mutations in CSF3R, in 2 unrelated families. The affected children in the first family harbored a homozygous missense mutation p.Arg308Cys, near the WSXWS motif, that resulted in abnormal G-CSFR glycosylation, impaired trafficking of the receptor to the cell surface, and reduced downstream signaling. The affected child in the second family carried compound heterozygous frameshift mutations that truncated the receptor in the extracellular domain (p.Gly316fsTer322 and p.Gly415fsTer432). None of the affected children in either family responded to treatment with recombinant G-CSF. Despite reduced numbers of circulating neutrophils, all the patients had morphological evidence of full myeloid cell maturation in the bone marrow.
Klimiankou et al PMID: 26324699 demonstrated the successful treatment of a CN patient harboring biallelic loss-of-function CSF3R mutations who did not respond to G-CSF by administering GM-CSF. The finding suggests that all CN patients who do not respond to G-CSF should be screened for germ-line CSF3R mutations, and treatment with GM-CSF should be considered. Klimiankou et al gives evidence for the third case of the novel genetic subtype of CN, termed CN-CSF3R, which supports the two other cases described by Triot et al PMID: 24753537.

Important to note that the missense variant NM_156039.3:c.1919C>A of CSF3R which is inherited in an autosomal dominant manner results in a thr617-to-asn (T617N) substitution gives rise to hereditary neutrophilia (MIM:162830) PMID:19620628, which this entry does not represent, this specific variant has been reported as an acquired activating mutation patients with acute myeloid leukemia PMID:12203110.

Created: 13 Mar 2017, 11:30 a.m.

Comment on list classification: Changed from Red to Green due to evidence in the literature.

Created: 28 Feb 2017, 11:05 a.m.

Comment on publications: More than three unrelated cases for severe congenital neutropenia-7 (MIM:617014) PMID: 24753537 (2 unrelated families, 3 affecteds) and PMID: 26324699 (1 family, 1 affected).

Created: 28 Feb 2017, 11:02 a.m.

Green List (high evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Severe congenital neutropenia

Publications

• 9001427

Variants in this GENE are reported as part of current diagnostic practice