SLC9A9 – Autism Spectrum Disorder

Rare variant analysis in an unselected cohort of 174 ASD patients identified SLC9A9 among five genes with a significant burden of rare variants, supporting its role in autism risk. However, no de novo occurrences or family segregation data have been reported, and the number of unrelated probands harboring SLC9A9 variants was not specified (PMID:31134136).

Functional studies provide moderate evidence for a loss‐of‐function mechanism. Yeast complementation and primary mouse cortical astrocyte assays demonstrated that autism‐associated missense substitutions L236S (p.Leu236Ser), S438P (p.Ser438Pro), and V176I (p.Val176Ile) fail to alkalinize endosomal pH and impair transferrin and glutamate uptake, recapitulating a hypomorphic phenotype (PMID:24065030). In contrast, three other SLC9A9 variants—c.1825C>A (p.Gln609Lys), c.1486G>A (p.Asp496Asn), and c.349C>A (p.Pro117Thr)—retained normal endosomal function in HEK293 cells, indicating variant‐specific effects (PMID:28815171).

Key take‐home: While rare SLC9A9 variants are implicated in ASD through cohort‐level association and mechanistic cellular data, further familial studies and larger case series are needed for definitive clinical utility.

References

• Frontiers in genetics • 2019 • Comprehensive Analysis of Rare Variants of 101 Autism-Linked Genes in a Hungarian Cohort of Autism Spectrum Disorder Patients. PMID:31134136
• Nature communications • 2013 • Functional evaluation of autism-associated mutations in NHE9. PMID:24065030
• Matters • 2017 • Functional analysis of Na+/H+ exchanger 9 variants identified in patients with autism and epilepsy. PMID:28815171

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