Bi-Allelic Variants in Neuronal Adhesion Molecule Astrotactin 1 Gene ASTN1 Cause Diverse Neurodevelopmental Disorders

Authors

• Jesse M Levine
• Daniel G Calame
• Riccardo Sangermano
• Haowei Du
• Ahmed Saad
• Jasmin Lisfeld
• Tatjana Bierhals
• Jonas Denecke
• Eyyup Uctepe
• Merve Yoldas Celik
• Ahmet Yesilyurt
• Hilal Yildiz Er
• Elif Yilmaz Gulec
• Aziza Mushiba
• Naif Almontashiri
• Pawel Gawlinski
• Wojciech Wiszniewski
• Ender Karaca
• Lama Alabdi
• Davut Pehlivan
• Dana Marafi
• Maha S Zaki
• Fowzan S Alkuraya
• Joseph G Gleeson
• Shalini N Jhangiani
• Richard A Gibbs
• Jennifer E Posey
• Kinga M Bujakowska
• James R Lupski

Language

English

Publication Date

2-5-2026

Journal

American Journal of Human Genetics

DOI

10.1016/j.ajhg.2025.12.011

PMID

41544630

PMCID

PMC13087404

PubMedCentral® Posted Date

5-7-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

ASTN1 encodes astrotactin 1, a neuronal-glial ligand in the developing brain that promotes neuronal migration along radial glia in brain structures with laminar organization, such as the cerebral cortex, hippocampus, and cerebellum. In mouse models, disruption of Astn1 results in neuronal migration deficits, a mild reduction in cerebellar volume, and balance and coordination deficits. In humans, bi-allelic ASTN1 variants have been identified in nine individuals with neurodevelopmental disorders (NDDs) with or without brain malformations. ASTN1 additionally interacts with astrotactin 2 (ASTN2) to implement neuronal migration; ASTN2 deletions associate with NDDs with reduced penetrance. Here, we describe eighteen individuals with NDDs from twelve unrelated families with bi-allelic, ultra-rare, predicted damaging variants in ASTN1 and one individual with heterozygous variants in both ASTN1 and ASTN2. We expand the clinical phenotypic descriptions of ASTN1-related NDDs, which range from mild to profound developmental delay or intellectual disability and can be associated with autism, attention-deficient hyperactivity disorder (ADHD), and epilepsy. Other recurrent abnormalities include dysmorphic facial features, hypotonia, spasticity, and ataxia. Additionally, we add to the neuroradiographic phenotype of this condition, which can be normal, mildly dysmorphic (a thin corpus callosum and cerebellar dysgenesis), or severely dysmorphic (polymicrogyria and lissencephaly). Remarkably, three genetic models of multilocus pathogenic variation (MPV), including tri-allelic, double heterozygous, and double homozygous due to distributive absence of heterozygosity (AOH), were observed. This ASTN1 allelic series characterizes the consequences of perturbations in radial-glia-guided neuronal migration in humans, the phenotypic spectrum of ASTN1-related NDDs, and the contribution of MPV to the genetic basis of NDDs.

Keywords

Humans, Female, Male, Child, Alleles, Neurodevelopmental Disorders, Nerve Tissue Proteins, Child, Preschool, Adolescent, Pedigree, Phenotype, Cell Movement, Neurons, Infant, Animals, Mutation, Attention Deficit Disorder with Hyperactivity, Intellectual Disability, Glycoproteins

Published Open-Access

yes

Recommended Citation

Levine, Jesse M; Calame, Daniel G; Sangermano, Riccardo; et al., "Bi-Allelic Variants in Neuronal Adhesion Molecule Astrotactin 1 Gene ASTN1 Cause Diverse Neurodevelopmental Disorders" (2026). Faculty, Staff and Students Publications. 7135.
https://digitalcommons.library.tmc.edu/baylor_docs/7135