HAX1 – Severe Congenital Neutropenia

Autosomal recessive severe congenital neutropenia (SCN) associated with HAX1 deficiency is characterized by a maturation arrest of granulopoiesis at the promyelocyte stage, profound neutropenia, and recurrent life-threatening bacterial infections. Biallelic loss-of-function variants in HAX1 underlie Kostmann disease (SCN3) and define a distinct autosomal recessive form of congenital neutropenia.

Initial genetic evidence arose from positional cloning that identified a recurrent homozygous HAX1 mutation in three independent pedigrees and 19 additional affected individuals, with segregation of homozygous variants in extended families (22 probands) (PMID:17187068). Subsequent case reports confirmed compound heterozygous alleles such as c.568C>T (p.Gln190Ter) (PMID:19499579) and homozygous W44X (c.132G>A, p.Trp44Ter) in consanguineous siblings presenting with oral ulcers, candidiasis, and severe infections (PMID:20128427).

The variant spectrum comprises over 30 distinct biallelic HAX1 changes in more than 22 unrelated probands, mainly nonsense, frameshift, and splice-site mutations affecting both transcript variants. A representative pathogenic allele is c.568C>T (p.Gln190Ter), which truncates HAX1 and abolishes its mitochondrial function.

Functional studies demonstrate that HAX1 localizes to the mitochondrial inner membrane and protects myeloid cells from apoptosis by preserving membrane potential. HAX1 knock-out and patient-derived iPSC models recapitulate the neutrophil differentiation block and increased apoptosis, whereas lentiviral HAX1 expression or CRISPR-Cas9–mediated correction restores granulopoiesis and rescues apoptotic susceptibility (PMID:17187068, PMID:23975175, PMID:29296734).

No conflicting evidence has been reported regarding autosomal recessive HAX1 deficiency causing SCN; heterozygous carriers remain asymptomatic. Isoform-specific mutations correlate with the presence or absence of neurological features, refining the genotype–phenotype map.

Integration of robust genetic segregation and concordant functional data supports a definitive gene–disease relationship. HAX1 sequencing should be included in diagnostic panels for early-onset neutropenia to guide G-CSF therapy, inform prognosis, and enable genetic counseling.

Key Take-home: Biallelic HAX1 loss-of-function variants cause autosomal recessive SCN by impairing mitochondrial integrity in granulopoiesis, and genetic testing of HAX1 is essential in the diagnostic evaluation of congenital neutropenia.

References

• Nature Genetics • 2007 • HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease). PMID:17187068
• Haematologica • 2014 • Genetic correction of HAX1 in induced pluripotent stem cells from a patient with severe congenital neutropenia improves defective granulopoiesis. PMID:23975175
• Blood Advances • 2017 • Gene correction of HAX1 reversed Kostmann disease phenotype in patient-specific induced pluripotent stem cells. PMID:29296734

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