ATP9A and Intellectual Disability

ATP9A has been implicated in neurodevelopmental disorders, particularly intellectual disability, through evidence supporting both autosomal dominant and autosomal recessive transmission. Multiple independent studies have identified heterozygous missense variants as well as biallelic truncating/splicing variants in affected individuals, highlighting a dual mode of inheritance. These findings are relevant for diagnostic decision‑making, commercial assay development, and future research publications (PMID:40226306).

In one study, five de novo heterozygous missense variants were identified in patients with intellectual disability, with additional truncating variants identified in a separate family, suggesting a dominant inheritance pattern (PMID:40226306). In contrast, other reports have demonstrated that consanguineous families harbor biallelic variants including a canonical splicing variant (c.799+1G>T) and a truncating variant (c.868C>T (p.Arg290Ter)), establishing an autosomal recessive disease mechanism (PMID:34764295; PMID:34379057).

The genetic evidence is robust with multiple variant types across independent cohorts. In the autosomal dominant cases, the heterozygous missense alleles (e.g. p.(Thr393Arg), p.(Glu400Gln), p.(Lys461Glu), p.(Gly552Ala), and p.(His713Asp)) were associated with abnormalities in dendritic spine maturation, while the recessive studies identified splicing and truncating mutations affecting ATP9A expression and function. One representative variant from the recessive studies is c.868C>T (p.Arg290Ter), which meets full HGVS criteria and underscores the mutational spectrum (PMID:34379057).

Segregation analysis in affected families further supports these associations. The de novo occurrence of heterozygous missense variants in unrelated patients and the identification of homozygous or compound heterozygous mutations in consanguineous families offer complementary evidence. Although explicit counts of additional affected relatives have not been uniformly reported, the familial clustering in recessive cases and the recurrence of variants across studies emphasize a genetic etiology (PMID:34764295).

Functional studies provide important insights into the pathogenic mechanisms of ATP9A variants. Experimental overexpression of mutant forms in HeLa cells and neuronal cultures has demonstrated impaired dendritic spine formation and altered subcellular localization, consistent with abnormal endosomal recycling. Additionally, patient‐derived fibroblast assays and Atp9a null mouse models recapitulate key aspects of the neurodevelopmental phenotype, supporting a biological link between ATP9A dysfunction and impaired neuronal maturation (PMID:34379057; PMID:36604604).

Notably, the evidence reflects a dual inheritance pattern. The coexistence of de novo heterozygous missense variants causing a dominant phenotype alongside biallelic truncating variants leading to a recessive disorder suggests overlapping yet distinct pathogenic mechanisms. This complication necessitates careful interpretation in clinical settings and supports the need for comprehensive genetic testing and counseling.

In summary, the integration of genetic and functional data from multiple independent studies provides strong evidence that ATP9A variants are causally associated with intellectual disability. The convergence of findings from variant analyses, segregation studies, and robust functional assays supports a strong ClinGen gene‑disease association. This consolidated evidence offers a key take‑home message: accurate genetic diagnosis of ATP9A‐related disorders requires careful consideration of both dominant and recessive inheritance modes.

References

• Human Mutation • 2025 • Heterozygous Missense Variants in the ATPase Phospholipid Transporting 9A Gene, ATP9A, Alter Dendritic Spine Maturation and Cause Dominantly Inherited Nonsyndromic Intellectual Disability PMID:40226306
• NPJ Genomic Medicine • 2021 • Biallelic Truncation Variants in ATP9A are Associated with a Novel Autosomal Recessive Neurodevelopmental Disorder PMID:34764295
• Journal of Medical Genetics • 2022 • Biallelic Truncating Variants in ATP9A Cause a Novel Neurodevelopmental Disorder Involving Postnatal Microcephaly and Failure to Thrive PMID:34379057
• Molecular Psychiatry • 2023 • ATP9A Deficiency Causes ADHD and Aberrant Endosomal Recycling via Modulating RAB5 and RAB11 Activity PMID:36604604

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