Congenital Hypotonia, Epilepsy, Developmental Delay, and Digital Anomalies (CHEDDA) via the ATN1 Gene

Pathogenic variants in the ATN1 gene are associated with congenital hypotonia, epilepsy, developmental delay, and digital anomalies (CHEDDA), a severe neurodevelopmental disorder (Palmer et al. 2019. PubMed ID: 30827498). Clinical features may include dysmorphic facial features, otitis media and/or hearing impairment, gastrointestinal disturbances, persistent fetal pads and/or overlapping fingers and toes, seizures, severe developmental delay, poor or absent speech, structural brain findings, as well as additional variable congenital anomalies (Palmer et al. 2019. PubMed ID: 30827498). Structural brain findings may include polymicrogyria, cerebral atrophy, thin corpus callosum, absent falx cerebri, and cerebellar vermis hypoplasia. Additional congenital anomalies may include cardiac, genitourinary, and skeletal malformations. It should be noted that only a limited number of cases have been described in the literature. The clinical spectrum for this disorder may be broader that currently described. The differential diagnosis for affected individuals in the literature has included syndromic polymicrogyria, Shprintzen-Goldberg syndrome, Pallister-Killian Syndrome, and epileptic encephalopathy (Mosca et al. 2007. PubMed ID: 17067864; Palmer et al. 2019. PubMed ID: 30827498). Onset typically occurs in the first 3 months of life, although some individuals may present with clinical features in the antenatal period (Palmer et al. 2019. PubMed ID: 30827498). The exact prevalence of CHEDDA is presently unknown, but is considered rare. Genetic testing may aide in establishing a differential diagnosis and may assist reproductive planning.

In addition to CHEDDA, a pathogenic polyglutamine repeat expansion in the ATN1 gene is exclusively associated with Dentatorubral-Pallidoluysian Atrophy (DRPLA). DRPLA is a rare progressive neurodegenerative disorder characterized by myoclonus, epilepsy, cerebellar ataxia, choreoathetosis, psychiatric disturbances, and intellectual deterioration or dementia (Veneziano and Frontali. 2016. PubMed ID: 20301664). CHEDDA differs from DRPLA in that it is non-progressive and characterized by congenital anomalies (Palmer et al. 2019. PubMed ID: 30827498).

Pathogenic variants in the ATN1 gene are associated with autosomal dominant CHEDDA. To date, all reported pathogenic variants have occurred de novo. Causative missense variants and in-frame insertions have been reported (Palmer et al. 2019. PubMed ID: 30827498). These variants cluster in a highly evolutionarily conserved histidine-rich amino acid motif in exon 8 of the ATN1 gene (Palmer et al. 2019. PubMed ID: 30827498). Although the exact function of this region is presently unknown, it is hypnotized to be critical for human embryonic development (Palmer et al. 2019. PubMed ID: 30827498).

The ATN1 gene encodes the atrophin-1 protein, a transcriptional corepressor involved in nuclear signaling that is widely expressed in the central nervous system and other tissues (Shen et al. 2007. PubMed ID: 17150957). The exact function of the ATN1 protein is yet to be fully elucidated. However, various animal models exist for the DRPLA-associated repeat expansion. These models suggest a gain of function mechanism where neuronal intranuclear accumulation of the elongated protein leads to progressive brain atrophy and neuronal dysfunction (Saki et al. 2006. PubMed ID: 16891319; Sato et al. 2009. PubMed ID: 19039037). Interestingly, ATN1 null mice are reported to be viable, healthy and fertile, which suggest that loss of ATN1 function is unlikely to be a disease mechanism (Shen et al. 2007. PubMed ID: 17150957).

The clinical sensitivity of CHEDDA is difficult to estimate, as to date only a limited number of cases have been described in the literature (Palmer et al. 2019. PubMed ID: 30827498). De novo variants in the ATN1 gene are reported to explain 1 out of 6,100 clinical exome cases with a neurological phenotype and 5 out of 13,460 clinical exome cases with a neurodevelopmental phenotype (Palmer et al. 2019. PubMed ID: 30827498).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the ATN1 gene plus 10 bases flanking noncoding DNA in all available transcripts in addition to non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).

Note that this test does not include analysis of the DRPLA-associated ATN1 CAG repeat expansion. Please see our DRPLA ATN1 CAG repeat expansion test.