ATN1

Inheritance Pattern: AD

Disease ID:MONDO:0032781

Submitter: Illumina

The ATN1 gene is located on chromosome 12 at 12p13.31 and encodes the atrophin1 protein, which is a transcriptional corepressor that regulates development of the brain and other organs. ATN1 was first reported in relation to autosomal dominant congenital hypotonia, epilepsy, developmental delay, and digit abnormalities (CHEDDA) in 2019 (30827498: Palmer et al. 2019). At least eight unique variants, including six missense and two in-frame insertions, have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and limited experimental data. Variants in this gene have been reported in eight probands from a single publication (30827498: Palmer et al. 2019). All variants were heterozygous and occurred de novo. The maximum score for genetic evidence (12 pts.) has been reached, but additional reports in humans are needed to replicate the initial finding. The mechanism of disease is currently unclear; Palmer et al. (2019) speculate that disruption of the regular spacing of histidines in the HX repeat motif may alter interactions important for the disease process. Of note, this gene has also been implicated in dentatorubral-pallidoluysian atrophy. This association will be assessed separately. The association with CHEDDA is supported by limited experimental evidence involving the gene product's function. ATN1 is an atrophin protein family member and a transcriptional corepressor (19043594: Wang et al. 2008). Another atrophin family member, RERE, is associated with a disorder with significant overlap with CHEDDA (27087320: Fregeau et al. 2016), and other genes containing similar histidine repeat motifs, which is the domain affected by all variants reported to date, have also been linked to neurocognitive conditions with congenital anomalies (30827498: Palmer et al. 2019). In addition, ATN1 is regulated by LSD1, which is also associated with a similar clinical phenotype (25519973: Zhang et al. 2014). ATN1 is expressed broadly in multiple organs, including brain, heart, lung, kidney, and skeletal muscle, and expression is higher in fetal tissue, including in neural progenitors (25519973: Zhang et al. 2014). In utero electroporation experiments demonstrate that ATN1 maintains neural progenitor cells in mouse neocortex (25519973: Zhang et al. 2014). In summary, there is moderate evidence to support this gene-disease relationship. While more expertimental evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. Congenital hypotonia, epilepsy, developmental delay, and digital anomalies, MIM 618494 Dentatorubral-pallidoluysian atrophy, MIM 125370 Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in disease mechanism and phenotype. Palmer et al. (2019) (PMID: 30827498) proposed a new gene-disease relationship for the ATN1 gene based on the identification of eight patients with de novo missense or in-frame insertion variants in the HX repeat region of ATN1. The suggested phenotype name was CHEDDA (congenital hypotonia, epilepsy, developmental delay, digit abnormalities) and patients displayed severe cognitive impairment, hypotonia, a recognizable facial gestalt, and variable congenital anomalies. All patients lacked the progressive symptoms of dentatorubral-pallidoluysian atrophy (DRPLA) neurodegeneration (OMIM: 125370). DRPLA is caused by heterozygous expanded trinucleotide repeats in ATN1. Therefore, we have split curations for the disease entities CHEDDA and DRPLA. 

Inheritance Pattern: AD

Disease ID:MONDO:0007435

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0032781

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0032781

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0007435

Submitter: ClinGen

*ATN1* was first reported in relation to autosomal dominant dentatorubral-pallidoluysian atrophy (DRPLA) in 1994 (Koide R *et al.* PMID:8136840 and Burke JR *et al.* PMID: 7951323). Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare neurodegenerative disorder caused expanded CAG repeats in the ATN1 gene, with affected individuals commonly reported to have 48 or more repeat units (https://www.ncbi.nlm.nih.gov/books/NBK583218/). In 2019, *ATN1* was reported in relation to autosomal dominant congenital hypotonia, epilepsy, developmental delay, digit abnormalities (CHEDDA) (Palmer E. *et al.* PMID: 30827498). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanism and phenotypic variability. Therefore, the following disease entities have been split into separate disease entities: Dentatorubral-pallidoluysian atrophy (MIM 125370) and Congenital Hypotonia, Epilepsy, Developmental delay, and digital anomalies (MIM 618494). This curation is to assess the relationship between *ATN1* and DRPLA. The split curation for *ATN1*-related CHEDDA will be assessed separately. Although *ATN1*-related DRPLA is most prevalent in the Japanese population (PMID: 36809552), affected individuals from other ethnic populations outside of Japan have been reported (PMIDs: 7951323, 9251070, 12925365, 34022586, 37243799 and doi:10.1016/j.jns.2019.10.1486). Individuals affected by DRPLA with homozygous *ATN1* CAG repeats and family history of consanguinity have been reported separately by Sato *et. al.* in 1995 and by Kurohara *et al.* in 1997 (PMIDs: 7477999 and 9109905), however, they were not included in this curation as there not been any recent reports of autosomal recessive cases of *ATN1*-related DRPLA and the majority of DRPLA patients reported in the literature showed heterozygous pathogenic expanded CAG repeats in *ATN1*, indicative of autosomal dominant inheritance. The mechanism of pathogenicity appears to be dominant negative mechanism as the expansion of polyglutamine residues in atrophin-1 impacts caspase cleavage of ATN1 and subsequent separation of N-terminal and C-terminal, resulting in C-terminal fragment mislocalization and pathogenic accumulation in the cytoplasm, ultimately leading to increased cellular toxicity in neurons (PMIDs: 21577324, 23933208). Seventeen *ATN1* expanded CAG variants with allele sizes over 48 repeats that have been reported in seventeen probands in nine publications (PMIDs: 7951323, 8136840, 9251070, 12925365, 28432641, 34022586, 37243799, 39181274, 40552560) are included in this curation. In addition, pathogenic expanded CAG repeats in *ATN1* have been reported to segregate with DRPLA in families (PMIDs: 7951323 and 39181274). This gene-disease relationship is also supported by animal and rescue models, tissue expression and in vitro studies (PMIDs: 22342974, 23715323, 34968706, 39921111). Transgenic mice and drosophila models displayed ataxia and reduction in mobility similar to human DRPLA patients (PMIDs: 22342974 and 39921111). Rescue experiments involving intracerebroventricular infusion of a CAG-specific small molecule, naphthyridine–azaquinolone, induced CAG repeat contraction in the striatum, diminished mutant ATN1 aggregation, reduced body weight loss, and improved motor coordination and balance in transgenic Q113 ATN1 mice (PMID: 34968706). Bulk tissue gene expression data from the GTEx Portal indicates *ATN1* is highly expressed in the brain among other tissues (PMID: 23715323, dbGaP Accession phs000424.v10.p2). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. In summary, there is definitive evidence supporting the relationship between *ATN1* and autosomal dominant DRPLA. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Cerebellar Ataxia GCEP on the meeting date May 13, 2026 (SOP Version 12).

Inheritance Pattern: AD

Disease ID:MONDO:0007435

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0032781

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0032781

Submitter: Labcorp Genetics (formerly Invitae)