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Multiple independent studies and case reports have established a strong association between homozygous mutations in JAGN1 and severe congenital neutropenia. The reported evidence encompasses over 20 unrelated probands with autosomal recessive inheritance, in which segregating variants have been identified across different families, supporting a robust gene‑disease association (PMID:25129144). The clinical cases consistently describe severe bacterial infections, oral ulcerations, recurrent respiratory and urinary tract infections, and in some instances congenital agranulocytosis and other systemic features.
Genetic evidence is underscored by several independent reports. In one study, next‑generation sequencing revealed the homozygous mutation c.63G>T (p.Glu21Asp) in the JAGN1 gene in a syndromic child with intermittent neutropenia, confirming its role in neutrophil differentiation and function (PMID:30044346). Additional case reports and multi‑patient studies have demonstrated a spectrum of pathogenic variants—including missense, loss‑of‑function and deletions—supporting the causative role of JAGN1 mutations in the observed phenotype.
Functional assessments further strengthen this association. Experimental studies using neutrophils from affected patients have revealed abnormal endoplasmic reticulum structure, impaired neutrophil extracellular trap formation, and reduced myeloperoxidase expression, consistent with the clinical presentation of severe congenital neutropenia (PMID:30106500). These functional studies, together with rescue experiments using granulocyte‑stimulating factors and calpain inhibition, provide a mechanistic rationale for the pathogenicity of mutated JAGN1.
The converging genetic and experimental findings support a strong gene‑disease relationship. While some functional studies indicate variability in response to growth factor treatments, the collective evidence from multiple families and experimental models exceeds the ClinGen scoring maximum, reinforcing the clinical utility of testing for JAGN1 mutations in patients with severe congenital neutropenia.
In clinical practice, the detection of mutations such as c.63G>T (p.Glu21Asp) in JAGN1 should prompt early genetic counselling and tailored management strategies. This is particularly critical given the high risk of life‑threatening infections associated with the disorder, and it emphasizes the importance of a multidisciplinary approach to optimize patient outcomes.
Key Take‑home sentence: Identification of pathogenic JAGN1 mutations provides a definitive diagnostic marker that is essential for the early detection and management of severe congenital neutropenia.
Gene–Disease AssociationStrongOver 20 unrelated probands with autosomal recessive inheritance, multiple segregating variants, and convergent functional data provide robust evidence for a strong gene‑disease association (PMID:25129144). Genetic EvidenceStrongMultiple independent reports identified pathogenic variants, including c.63G>T (p.Glu21Asp), in patients with severe congenital neutropenia, with clear segregation across families (PMID:30044346). Functional EvidenceModerateFunctional studies demonstrate abnormal ER structure, reduced MPO expression, and impaired NET formation in JAGN1‑deficient neutrophils, supporting the pathogenic mechanism (PMID:30106500). |