NNAT – Anorexia Nervosa

The association between NNAT and anorexia nervosa has been investigated in multiple studies using next generation sequencing panels and family segregation analyses. Several independent reports have identified rare deleterious variants in NNAT among individuals diagnosed with anorexia nervosa, supporting the gene’s involvement in disease etiology (PMID:34822136, PMID:30933048). These observations have been replicated in different cohorts with both male and female patients, and the testing strategy has included both case series and targeted segregation studies.

Family segregation analyses have further bolstered the role of NNAT in anorexia nervosa. In one study, a truncating variant was detected and segregated in affected family members, providing critical supportive evidence (PMID:30933048). The identification of such variants in unrelated probands—along with segregation of the variant in affected relatives—strengthens the clinical validity of the association.

Genetic evidence includes a spectrum of variants reported in NNAT, with a notable example being the truncating change c.99G>A (p.Trp33Ter). This variant was identified in a proband and is supported by additional findings of rare coding and regulatory region alterations in NNAT from independent studies (PMID:34822136). Collectively, these genetic findings contribute to a robust picture of pathogenic variation in NNAT associated with anorexia nervosa.

Functional and experimental evidence also underscore NNAT’s role in disease pathology. In silico analyses have revealed that specific rare-coding variants, such as a damaging change predicted from modeling studies, can alter NNAT protein conformation and function (PMID:35655118). Although these studies primarily utilized computational approaches, the results correlate well with the clinical phenotype and support a mechanistic role for NNAT disruption in neuronal calcium regulation and related cellular pathways.

Integrating the genetic and functional data, the evidence supports a strong association between NNAT and anorexia nervosa. Multiple independent cohorts have reported deleterious NNAT variants with demonstrable segregation in affected families, and functional studies provide converging evidence of an impact on protein function. While additional research may further extend the available evidence beyond the current scoring cap, the present data clearly indicate clinical utility in considering NNAT as a diagnostic marker in anorexia nervosa.

Key take‐home: The consistent detection of pathogenic NNAT variants in affected individuals, combined with supportive functional data, reinforces the role of NNAT in anorexia nervosa and underscores its potential as a valuable tool for diagnostic decision‑making and personalized management.

References

• Eating and weight disorders : EWD • 2022 • A next generation sequencing gene panel for use in the diagnosis of anorexia nervosa PMID:34822136
• Psychiatric genetics • 2019 • Anorexia nervosa is associated with Neuronatin variants PMID:30933048
• Eating and weight disorders : EWD • 2022 • In silico identification of the rare-coding pathogenic mutations and structural modeling of human NNAT gene associated with anorexia nervosa PMID:35655118

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