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

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
13017 ATN1 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
13017ATN181479 81479 $890 Order Options and Pricing

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

For Reflex to PGxome pricing click here.

Turnaround Time

18 days on average for standard orders or 14 days on average for STAT orders.

Once a specimen has started the testing process in our lab, the most accurate prediction of TAT will be displayed in the myPrevent portal as an Estimated Report Date (ERD) range. We calculate the ERD for each specimen as testing progresses; therefore the ERD range may differ from our published average TAT. View more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

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).

Genetics

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).

Clinical Sensitivity - Sequencing with CNV PGxome

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).

Testing Strategy

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.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

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.

Indications for Test

Candidates for this test are patients with clinical features consistent with a diagnosis of congenital hypotonia, epilepsy, developmental delay, and digital anomalies (CHEDDA). Targeted testing is indicated for family members of patients who have a known pathogenic variant in ATN1.

Gene

Official Gene Symbol OMIM ID
ATN1 607462
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Test

Name
Dentatorubral-Pallidoluysian Atrophy (DRPLA) via the ATN1 CAG Repeat Expansion

Citations

  • Mosca et al. 2007. PubMed ID: 17067864
  • Palmer et al. 2019. PubMed ID: 30827498
  • Sakai et al. 2006. PubMed ID: 16891319
  • Sato et al. 2009. PubMed ID: 19039037
  • Shen et al. 2007. PubMed ID: 17150957
  • Veneziano and Frontali. 2016. PubMed ID: 20301664

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


Specimen Types

Specimen Requirements and Shipping Details

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ORDER OPTIONS

View Ordering Instructions

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2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

No Additional Test Options are available for this test.

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