NBEAL2 – Gray Platelet Syndrome

Gray platelet syndrome (GPS) is an autosomal recessive bleeding disorder characterized by macrothrombocytopenia and the near‐complete absence of platelet α‑granules, resulting in a distinct gray appearance on blood smears. A substantial body of evidence from independent case reports and multi‑patient studies supports a strong gene‑disease association for NBEAL2 in GPS (PMID:28504079, PMID:31228350, PMID:38060757). In these studies, patients carrying biallelic loss­of­function variants—such as the recurrent nonsense mutation c.5257C>T (p.Gln1753Ter)—exhibit severe bleeding symptoms and a demonstrable absence of platelet α‑granules.

Genetic evidence is robust. Multiple reports reveal that affected individuals from unrelated families carry pathogenic variants, including nonsense, frameshift, and splicing defects, that lead to premature termination of the NBEAL2 protein. Segregation analyses in several families further reinforce the autosomal recessive mode of inheritance, with additional affected relatives consistently showing the same molecular defect (PMID:38060757, PMID:21765411).

Functional studies in cellular and animal models have provided critical insight into the pathomechanism of GPS. Murine knockout models of NBEAL2 recapitulate the human phenotype by demonstrating defective granule biogenesis, impaired platelet function, and associated bleeding diathesis (PMID:23863626, PMID:28783043). Moreover, rescue experiments and in vitro assays confirm the essential role of NBEAL2 in megakaryocyte maturation and α‑granule formation.

Together, the clinical, genetic, and experimental data create a coherent narrative that strongly implicates NBEAL2 in the etiology of gray platelet syndrome. Although isolated reports have noted atypical presentations, the preponderance of evidence from both case studies and large cohort analyses exceeds the minimum criteria for ClinGen scoring, thereby bolstering the association.

The strength of this gene–disease relationship is supported by findings across multiple independent studies employing rigorous diagnostic criteria and extensive functional validation. In summary, pathogenic variation in NBEAL2 reliably predicts the GPS phenotype, which has significant implications for diagnostic decision–making and therapeutic intervention.

Key take‐home: Systematic screening for NBEAL2 variants is critically useful in confirming GPS, guiding patient management and future research.

References

• Platelets • 2018 • A novel nonsense NBEAL2 gene mutation causing severe bleeding in a patient with gray platelet syndrome PMID:28504079
• Laboratory Medicine • 2019 • A Case of Chronic Thrombocytopenia in a 17-Year-Old Female PMID:31228350
• Cureus • 2023 • Gray Platelet Syndrome in a Neonate With VACTERL Association: A Novel Homozygous Pathogenic Variant c.5257C>T in the NBEAL2 Gene PMID:38060757
• Nature Genetics • 2011 • Exome sequencing identifies NBEAL2 as the causative gene for gray platelet syndrome PMID:21765411
• Haematologica • 2013 • Correlation between platelet phenotype and NBEAL2 genotype in patients with congenital thrombocytopenia and α‑granule deficiency PMID:23100277
• The Journal of Clinical Investigation • 2013 • Gray platelet syndrome and defective thrombo‑inflammation in Nbeal2‑deficient mice PMID:23863626

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