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.