Document Type

Article

Publication Date

11-2024

Identifier

DOI: 10.1111/cge.14587; PMCID: PMC11444875

Abstract

ANK3 encodes ankyrin-G, a protein involved in neuronal development and signaling. Alternative splicing gives rise to three ankyrin-G isoforms comprising different domains with distinct expression patterns. Mono- or biallelic ANK3 variants are associated with non-specific syndromic intellectual disability in 14 individuals (seven with monoallelic and seven with biallelic variants). In this study, we describe the clinical features of 13 additional individuals and review the data on a total of 27 individuals (16 individuals with monoallelic and 11 with biallelic ANK3 variants) and demonstrate that the phenotype for biallelic variants is more severe. The phenotypic features include language delay (92%), autism spectrum disorder (76%), intellectual disability (78%), hypotonia (65%), motor delay (68%), attention deficit disorder (ADD) or attention deficit hyperactivity disorder (ADHD) (57%), sleep disturbances (50%), aggressivity/self-injury (37.5%), and epilepsy (35%). A notable phenotypic difference was presence of ataxia in three individuals with biallelic variants, but in none of the individuals with monoallelic variants. While the majority of the monoallelic variants are predicted to result in a truncated protein, biallelic variants are almost exclusively missense. Moreover, mono- and biallelic variants appear to be localized differently across the three different ankyrin-G isoforms, suggesting isoform-specific pathological mechanisms.

Journal Title

Clinical genetics

Volume

106

Issue

5

First Page

574

Last Page

584

MeSH Keywords

Humans; Ankyrins; Male; Female; Phenotype; Alleles; Child; Intellectual Disability; Child, Preschool; Genotype; Adolescent; Autism Spectrum Disorder; Mutation; Adult; Genetic Association Studies; Genetic Predisposition to Disease; Attention Deficit Disorder with Hyperactivity; Epilepsy; Infant; Language Development Disorders

Keywords

aggressivity; ankyrin‐G; autism spectrum disorder; epilepsy; hypotonia; intellectual disability; language delay; neurodevelopmental disorder; sleep disturbances

Comments

Grants and funding

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Publisher's Link: https://onlinelibrary.wiley.com/doi/10.1111/cge.14587

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