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This summary evaluates the association between the neuron‑derived neurotrophic factor (NDNF) gene and Kallmann syndrome. In a recently reported case, a 14‑year‑old boy with Kallmann syndrome was found to harbor a novel homozygous nonsense variant in NDNF, providing critical insight into the disease mechanism (PMID:36454653). The clinical presentation, characterized by pubertal failure and olfactory defects, aligns with the expected features of Kallmann syndrome.
Genetic evidence demonstrates autosomal recessive inheritance. Segregation analysis using Sanger sequencing confirmed that the affected individual carried the homozygous variant while his heterozygous parents exhibited normal pubertal development (PMID:36454653). This segregation, alongside the complete absence of the variant in reference population databases, solidifies the variant’s pathogenicity.
The reported variant, c.1251C>A (p.Tyr417Ter), is a clear example of a truncating mutation resulting in a loss‑of‑function effect. Functional assessments indicate that the absence of full‐length NDNF protein disrupts neurotrophic signaling, a key pathway implicated in the olfactory and reproductive abnormalities observed in Kallmann syndrome (PMID:36454653).
Additional multi‑patient studies have identified NDNF among several genes implicated in idiopathic hypogonadotropin hypogonadism. Although these studies reported a spectrum of variants, the case of the homozygous truncating mutation in NDNF offers direct evidence for its involvement in Kallmann syndrome, complementing broader analyses that explore gene variant distributions in affected cohorts (PMID:36245975).
Collectively, the clinical, genetic, and functional evidence indicates that inactivating mutations in NDNF contribute to Kallmann syndrome through a loss‑of‑function mechanism. Nonetheless, while the current data are compelling, further independent cases would enhance the association score.
Key take‑home sentence: The detection of a homozygous truncating NDNF variant provides actionable evidence for the diagnosis of Kallmann syndrome, supporting both clinical decision‑making and future therapeutic strategies.
Gene–Disease AssociationModerateA homozygous truncating NDNF variant was observed in a 14‑year‑old KS proband with robust segregation evidence and supportive functional data (PMID:36454653), with additional supportive observations from multi‑patient studies (PMID:36245975). Genetic EvidenceModerateThe identification of the c.1251C>A (p.Tyr417Ter) variant, its absence from control databases, and confirmatory segregation analysis collectively provide moderate genetic evidence for a role of NDNF in Kallmann syndrome (PMID:36454653). Functional EvidenceModerateExperimental data demonstrate that the truncating mutation abolishes NDNF function, which is concordant with the observed KS phenotype, thereby supporting a loss‑of‑function mechanism (PMID:36454653). |