Submission Details

The ANK3 gene encodes a protein belonging to the Ankryin family, which anchors membrane proteins to the underlying spectrin-actin cytoskeleton. Brain-specific isoforms of ANK3 are localized at the nodes of Ranvier and the axon initial segment and are involved in the clustering of voltage-gated ion channels required for the generation and propagation of action potentials. ANK3 was first reported in relation to autosomal recessive intellectual disability in 2013 (Iqbal et al., PMID: 23390136). Clinical findings include developmental delay, intellectual disability, behavioral problems, seizures, and brain imaging abnormalities. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanism, inheritance pattern and phenotypic variability. Therefore, the curation was split by inheritance pattern. This curation focuses on the relationship between ANK3 and autosomal recessive intellectual disability. The split curation for autosomal dominant complex neurodevelopmental disorder has been curated separately. Three homozygous frameshift variants in this gene have been reported in six affected individuals from three families in three publications (PMIDs: 23390136, 29302074, 32404165). In addition, ten homozygous or compound heterozygous missense variants, most lacking functional evidence of pathogenicity, have been reported in seven families (PMIDs: 26539891, 31451636, 3677705, 38988293). ANK3 is highly constrained both for loss-of-function and missense variants. The mechanism of pathogenicity is biallelic loss-of-function, which has been suggested to be isoform-specific. ANK3 encodes three major isoforms: the widely expressed 190 kDa isoform, and the 270 and 480 kDa isoforms, which are primarily expressed in the brain. Recessive variants affect the giant exon domain, which is present only in the longest, 480 kDa isoform, whereas dominant truncating variants are located in the N-terminal domain and disrupt all three transcripts (PMIDs: 34218362, 38988293). Individuals with biallelic variants exhibit a more severe phenotype than those with monoallelic variants (PMID: 38988293). The gene-disease relationship is also supported by experimental evidence, including animal models in mice (PMID: 25552556) and Drosophila (PMID: 18439406, 23390136). In summary, there is moderate evidence supporting the relationship between ANK3 and autosomal recessive intellectual disability. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on October 7, 2020 (SOP Version 7). It was reevaluated on October 2, 2024 (SOP Version 11). Although additional families were curated, only one had biallelic loss-of-function variants (PMID: 32404165), and the classification did not change.

The ANK3 gene encodes a member of the ankyrin family, which anchors membrane proteins to the underlying spectrin-actin cytoskeleton. Brain-specific isoforms of ANK3 are localized at the nodes of Ranvier and the axon initial segment and are involved in the clustering of voltage-gated ion channels required for the generation and propagation of action potentials. ANK3 was first reported in relation to autosomal recessive intellectual disability in 2013 (Iqbal et al., PMID: 23390136). Clinical findings include developmental delay, intellectual disability, behavioral problems, seizures, and brain imaging abnormalities. Heterozygous ANK3 variants have also been reported in individuals with neurodevelopmental disorders. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found differences in molecular mechanism, inheritance pattern and phenotypic variability. Therefore, the curation was split by inheritance pattern. This curation focuses on the relationship between ANK3 and autosomal recessive intellectual disability. The split curation for autosomal dominant complex neurodevelopmental disorder has been curated separately.

Three homozygous frameshift variants in this gene have been reported in six affected individuals from three families in three publications (PMIDs: 23390136, 29302074, 32404165). In addition, ten homozygous or compound heterozygous missense variants, most lacking functional evidence of pathogenicity, have been reported in seven families (PMIDs: 26539891, 31451636, 3677705, 38988293). ANK3 is highly constrained both for loss-of-function and missense variants. The mechanism of pathogenicity is biallelic loss of function, which has been suggested to be isoform-specific. ANK3 encodes three major isoforms: the widely expressed 190  kDa isoform, and the 270 and 480  kDa isoforms, which are primarily expressed in the brain. Recessive variants affect the giant exon domain, which is present only in the longest, 480 kDa isoform, whereas dominant truncating variants are located in the N-terminal domain and disrupt all three transcripts (PMIDs: 34218362, 38988293). Individuals with biallelic variants exhibit a more severe phenotype than those with monoallelic variants (PMID: 38988293).

This gene-disease relationship is also supported by experimental evidence, including animal models in mice (PMID: 25552556) and Drosophila (PMIDs: 18439406, 23390136).

In summary, there is moderate evidence supporting the relationship between ANK3 and autosomal recessive intellectual disability. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on October 7, 2020. It was reevaluated on October 2, 2024 (SOP Version 11). Although additional families were curated, only one had biallelic loss-of-function variants (PMID: 32404165), and the classification did not change.