The ANK2 gene codes for ankyrin-B (ANKB), a protein that links membrane proteins to the cytoskeleton, influencing cell stability and form. ANKB plays a key role in maintaining membrane ion channels and receptors, particularly in neurons and cardiac cells, affecting excitability and synaptic development. Its large neuronal isoform, giant ANKB (gANKB), is primarily made in the neonatal brain and declines with age, while the shorter isoform is widely present in the heart and nerve cells after birth. The ANK2 variantsare linked to cardiac conduction diseases and have been linked with autism spectrum disorders and, more rarely, epilepsy. Despite ANKB’s critical neuronal functions, epilepsy linked to ANK2 remains underreported.
A Taiwanese family with epilepsy was studied using exome sequencing (ES). Sequencing was performed using Illumina platforms, and variant analysis was conducted with Geneyx software. After filtering against the gnomAD database and evaluating variant severity using multiple prediction algorithms, five variants remained, with only one shared by both the index case and her impacted brother. Additionally, a review identified 43 “pathogenic” or “likely pathogenic” ANK2 variants from ClinVar and 18 from UniProt. After excluding large structural variants and entries lacking phenotypic data, 32 variants remained and were categorized by phenotype: cardiovascular, neurodevelopmental disorders, seizures/epilepsy, and others. A PubMed review further included ANK2-related epilepsy cases.
Discover the full case report on developmental and epileptic encephalopathy linked to a de novo CLCN4 variant in a young Italian woman—read more here.
The ES of a Taiwanese family identified a novel ANK2 frameshift variant (c.6933del, p.T2312Lfs*2) affecting the neuron-specific gANKB isoform. The index case, a 24-year-old female, had epilepsy with seizures starting at 6 years of age. Her seizures resolved after 14 years of age. Her older brother had a similar clinical course, with seizures beginning at age 7 and resolving after adolescence. Their mother, an asymptomatic carrier, showed borderline QT prolongation. This supports dominant inheritance. Among 32 reviewed ANK2 pathogenic/likely pathogenic variants, all loss-of-function (LOF) variants were associated with central nervous system phenotypes such as neurodevelopmental disorders or epilepsy, while missense variants were linked to cardiovascular phenotypes. Of 10 known ANK2-related epilepsy cases (including this family), most presented with early-onset.
In summary, this study reports an ANK2 frameshift variant (c.6933del, p.T2312Lfs*2) in a Taiwanese family with epilepsy. This family’s phenotype was neurologically predominant, supporting ANK2 role in epileptogenesis. Literature review shows that all epilepsy-related ANK2 variants are LOF. These LOF variants disrupt calcium channel function and synaptic transmission, contributing to seizures. The expression of gANKB decreases with age, possibly explaining age-related seizure remission. Given mild epilepsy phenotypes without clear cardiac or autism spectrum features, ANK2-related epilepsy may be underrecognized, highlighting the need for genetic testing and cardiac monitoring to prevent complications.
