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ANKS1B – Neurodevelopmental Disorder

ANKS1B haploinsufficiency has emerged as a candidate cause of neurodevelopmental disorders based on a genome-wide a-CGH study of 1,800 Italian patients, in which pathogenic CNVs encompassing ANKS1B were identified, although the number of affected probands is unspecified (PMID:38674362). To date, no familial segregation beyond de novo occurrence has been reported, and specific variant-level data are lacking, limiting genetic resolution.

Functional models support a haploinsufficiency mechanism: Anks1b haploinsufficiency in mice recapitulates white matter and social behavior deficits analogous to those in patients, with rescue by clemastine (PMID:38129387). Comparative proteomic analysis of Anks1b-haploinsufficient synapses reveals altered Rac1 signaling within oligodendrocytes (PMID:37255534), while biochemical and structural studies elucidate high-affinity interactions between AIDA-1 and SynGAP, linking ANKS1B to synaptic Ras-GAP regulation (PMID:38759928). Together, these data provide moderate functional evidence for ANKS1B involvement in neurodevelopmental pathology.

Key Take-home: ANKS1B haploinsufficiency likely contributes to neurodevelopmental disorders via disrupted synaptic and oligodendrocyte pathways, supporting its consideration in diagnostic genetic testing.

References

  • Genes • 2024 • Genetic Alterations in a Large Population of Italian Patients Affected by Neurodevelopmental Disorders PMID:38674362
  • Nature communications • 2023 • ANKS1B encoded AIDA-1 regulates social behaviors by controlling oligodendrocyte function PMID:38129387
  • Frontiers in aging neuroscience • 2023 • Comparing synaptic proteomes across five mouse models for autism reveals converging molecular similarities including deficits in oxidative phosphorylation and Rho GTPase signaling PMID:37255534
  • Journal of molecular biology • 2024 • AIDA-1/ANKS1B Binds to the SynGAP Family RasGAPs with High Affinity and Specificity PMID:38759928
  • The Journal of cell biology • 1997 • Mal3, the fission yeast homologue of the human APC-interacting protein EB-1 is required for microtubule integrity and the maintenance of cell form PMID:9348288

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Single CNV cohort identified ANKS1B alterations without specific proband counts ([PMID:38674362]); limited segregation data

Genetic Evidence

Limited

One a-CGH study reports pathogenic CNVs in ANKS1B ([PMID:38674362]); no detailed variant-level or segregation data

Functional Evidence

Moderate

Anks1b haploinsufficiency models recapitulate neurodevelopmental phenotypes with rescue experiments; structural and biochemical assays define pathogenic mechanism ([PMID:38129387]; [PMID:37255534]; [PMID:38759928])