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Severe congenital neutropenia (SCN), also known as Kostmann syndrome, is a rare autosomal recessive disorder of neutrophil production characterized by marked neutropenia, recurrent infections, and risk of life-threatening bacterial sepsis. Biallelic mutations in HAX1 (HGNC:16915) underlie the SCN3 subtype, historically described in the original Swedish pedigree by Kostmann. The disorder manifests in infancy with absolute neutrophil counts often <0.2 × 10^9/L, arrest of granulopoiesis at the promyelocyte stage, and an infectious phenotype ameliorated by G-CSF therapy or curative hematopoietic stem cell transplantation.
Initial case reports identified homozygous and compound heterozygous HAX1 mutations in affected patients. A Swedish patient carried c.568C>T (p.Gln190Ter) and c.91delG (p.Glu31LysfsTer54) alleles leading to early stop codons, presenting with chronic neutropenia but no neurodevelopmental deficits (PMID:19499579). Subsequent reports highlighted dental complications and weight loss in Kostmann syndrome and rare co-occurrence with other disorders without altering the neutropenic phenotype.
A landmark multi-patient study using positional cloning identified a recurrent homozygous HAX1 mutation in three pedigrees and screened 19 additional affected individuals, totaling 22 probands with biallelic loss-of-function variants and confirming autosomal recessive inheritance (PMID:17187068). A Japanese cohort study of 18 SCN patients found five with HAX1 deficiency, including three with homozygous c.256C>T (p.Arg86Ter) and two siblings with compound heterozygosity, all exhibiting developmental delay and seizures (PMID:18611981). Segregation across five affected relatives supports pathogenicity.
The HAX1 variant spectrum is dominated by nonsense and frameshift mutations that truncate the mitochondrial protein, including c.568C>T (p.Gln190Ter), splice-site defects, and multi-exon deletions. Recurrent alleles such as c.430dupG (p.Val144fs) are notable in specific populations. No pathogenic missense variants with confirmed functional impact have been consistently reported.
Functional assays demonstrate that HAX1 is essential for maintaining inner mitochondrial membrane potential and protecting myeloid progenitors from apoptosis. HAX1 deficiency leads to increased apoptosis in neutrophil precursors, recapitulated in patient-derived iPSCs carrying the W44X mutation. CRISPR-Cas9 correction of HAX1W44X restored neutrophilic differentiation and reestablished anti-apoptotic transcriptional networks in vitro (PMID:29296734).
Genotype-phenotype studies reveal isoform-dependent neurological involvement: mutations affecting both HAX1 transcripts cause seizures and intellectual disability, whereas variants sparing isoform B lead to isolated neutropenia. Variable expressivity underscores the importance of transcript analysis in diagnostic evaluation.
Integration of robust genetic segregation, extensive proband data over >15 years, and concordant functional evidence fulfills criteria for a Definitive gene-disease association. HAX1 mutation analysis is critical for early diagnosis, prognostic counseling, and guiding G-CSF therapy or HSCT decisions.
Key Take-home: Biallelic HAX1 loss-of-function variants cause autosomal recessive Kostmann syndrome with consistent neutropenia and variable neurological involvement, establishing HAX1 analysis as a clinically actionable diagnostic test.
Gene–Disease AssociationDefinitive22 probands across multiple pedigrees with segregation and concordant functional data Genetic EvidenceStrong22 probands with biallelic HAX1 mutations in unrelated families, segregation in 5 relatives [PMID:17187068;18611981] Functional EvidenceStrongHAX1 maintains mitochondrial membrane potential and prevents apoptosis; gene correction in iPSCs rescued phenotype [PMID:17187068;29296734] |