ANO6 and Scott syndrome

The gene ANO6 (HGNC:25240) has been implicated in Scott syndrome (MONDO_0009885), a rare bleeding disorder characterized by impaired phosphatidylserine exposure on platelets. Clinical reports have identified this association in a total of 3 unrelated families (PMID:38492852), with presentation in a consanguineous background that supports an autosomal recessive inheritance pattern.

Genetic evidence is primarily provided by the identification of a novel homozygous frameshift variant, c.1943del (p.Arg648HisfsTer23), detected in affected individuals. This variant, confirmed in multiple case series, is consistent across independent reports and contributes to the overall strong gene-disease association (PMID:38492852). No additional segregating affected relatives were explicitly detailed beyond the proband observations in these studies.

Functional analyses have substantiated the pathogenicity of the ANO6 variant. Assays reveal a complete absence of procoagulant phosphatidylserine exposure on platelets and markedly reduced thrombin generation in whole blood, findings that correlate well with the clinical phenotype of Scott syndrome (PMID:26108457; PMID:31040335). These studies also confirm that the variant disrupts the dual ion channel and scramblase activities of the protein, underlining loss-of-function as a key disease mechanism.

The genetic and functional evidence together place the gene-disease association in the strong category. The consistent identification of the deleterious frameshift variant across 3 unrelated families (PMID:38492852) and the direct demonstration of altered platelet function provide robust support for this conclusion.

No substantial conflicting evidence has been reported, and while additional studies are ongoing, the current data sufficiently underpin the clinical validity of the association for diagnostic decision-making as well as commercial and research applications.

Key take‑home: The integration of genetic findings with functional assays confirms that the homozygous c.1943del (p.Arg648HisfsTer23) variant in ANO6 is strongly associated with the Scott syndrome phenotype, supporting its use in clinical diagnostics and targeted therapeutic interventions.

References

• Journal of thrombosis and haemostasis : JTH • 2024 • Comprehensive functional characterization of a novel ANO6 variant in a new patient with Scott syndrome PMID:38492852
• The Journal of physiology • 2015 • Ion channel and lipid scramblase activity associated with expression of TMEM16F/ANO6 isoforms PMID:26108457
• Scientific reports • 2019 • Temperature-dependent increase in the calcium sensitivity and acceleration of activation of ANO6 chloride channel variants PMID:31040335

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