The phenotypic and genotypic spectrum of individuals with mono- or biallelic ANK3 variants

Furia F, Levy AM, Theunis M, Bamshad MJ, Bartos MN, Bijlsma EK, Brancati F, Cejudo L, Chong JX, De Luca C, Dean SJ, Egense A, Goel H, Guenzel AJ, Hüffmeier U, Legius E, Mancini GM, Marcos-Alcalde I, Niclass T, Planes M, Redon S, Ros-Pardo D, Rouault K, Schot R, Schuhmann S, Shen JJ, Tao AM, Thiffault I, Van Esch H, Wentzensen IM, Barakat TS, Møller RS, Gomez-Puertas P, Chung WK, Gardella E, Tümer Z (2024)

Publication Type: Journal article

Publication year: 2024

Journal

DOI: 10.1111/cge.14587

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.

Authors with CRIS profile

Involved external institutions

Filadelfia Denmark (DK) University Hospital Leuven (UZ) / Universitaire ziekenhuizen Leuven Belgium (BE) Copenhagen University Hospital Denmark (DK) University of Washington United States (USA) (US) Cardiology PC United Kingdom (GB) Leiden University Medical Center Netherlands (NL) University of L'Aquila / Università degli Studi dell'Aquila Italy (IT) Centre hospitalier universitaire de Poitiers (CHU de Poitiers) France (FR) University of California Davis (UCDAVIS) United States (USA) (US) GeneDX United States (USA) (US) Erasmus University Medical Center (MC) Netherlands (NL) Centro de Biología Molecular Severo Ochoa (CBM) Spain (ES) Centre hospitalier universitaire de Brest (CHRU Brest) France (FR) Columbia University Irving Medical Center (CUIMC) United States (USA) (US) Children's Mercy Hospital United States (USA) (US) Boston Children's Hospital United States (USA) (US)

How to cite

APA:

Furia, F., Levy, A.M., Theunis, M., Bamshad, M.J., Bartos, M.N., Bijlsma, E.K.,... Tümer, Z. (2024). The phenotypic and genotypic spectrum of individuals with mono- or biallelic ANK3 variants. Clinical Genetics. https://doi.org/10.1111/cge.14587

MLA:

Furia, Francesca, et al. "The phenotypic and genotypic spectrum of individuals with mono- or biallelic ANK3 variants." Clinical Genetics (2024).

BibTeX: Download