Neuronal Ceroid Lipofuscinosis 12 via the ATP13A2 Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesPrice Test CPT CodeGene CPT Codes Copy CPT Codes
11097 ATP13A2$890 8147981479,81479 Add to Order

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information.

For Reflex to PGxome pricing click here.

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

Targeted Testing

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

Turnaround Time

18 days on average

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

The neuronal ceroid lipofuscinoses (NCLs) are inherited neurodegenerative lysosomal storage disorders caused by the accumulation of ceroid and lipofuscin in various cell types, mainly cells of the cerebral cortex, cerebellar cortex, and retina (Dyken et al. 1988; Williams and Mole 2012). Characteristic features at onset include clumsiness; deterioration of vision and psychomotor functions; seizures and behavioral changes. Progression of clinical features results ultimately in total disability, blindness and premature death. Although NCL affects primarily children, age of onset of symptoms varies from infancy to adulthood. The incidence of NCL is variable and ranges from 1.3 to 7 per 100,000 (Mole and Williams 2013). However, it is more common in northern European populations, particularly Finland where the incidence may reach 1 in 12,500 individuals and a carrier frequency of 1 in 70 (Rider and Rider 1988). NCLs are clinically and genetically heterogeneous. A nomenclature and classification based both on the age of onset of symptoms and the disease-causing gene has been recently developed, which classifies NCLs into thirteen subtypes (CLN1-8, 10-14) (Williams and Mole 2012). The causative gene for the CLN9 phenotype has not been identified yet (Schulz et al. 2004).

Of note, NCLs were previously known as Batten disease. However, in recent nomenclature, Batten disease only applies to NCL caused by pathogenic variants in CLN3.

CLN12 is characterized by juvenile onset and slow progression. To date, one single family with four affected individuals has been documented in the literature. Symptoms started around the age of 8 years with learning difficulties. As the disease progressed additional symptoms appeared and included bradykinesia, limb stiffness, gait disturbances, dysarthria, clumsiness, spasticity, myotonic jerks, seizures, slow eye movements, and peripheral neuropathy. MRI findings indicated brain atrophy. In this family, the diagnosis of neuronal ceroid lipofuscinosis was confirmed by the presence of lipofuscin deposits in post-mortem pathological studies of the brain and retina (De Volder et al. 1990; Bras et al. 2012).

Genetics

Most CLNs, including CLN12, are inherited in an autosomal recessive manner. Thirteen genes have been implicated in the disorder: PPT1, TPP1, CLN3, CLN5, CLN6, MFSD8, CLN8, CTSD, DNAJC5, CTSF, ATP13A2, GRN, and KCTD7 (Mole and Williams 2013).

CLN12 is caused by pathogenic variants in the ATP13A2 gene. A homozygous missense variant, c.2429T>G (p.Met810Arg), was found in the one reported family (Bras et al. 2012; De Volder et al. 1990). Support for the pathogenicity of this variant include its segregation with the disease in the described family; and its absence from control populations in various databases. Importantly, a homozygous truncating variant, c.1620delG, in the ATP13A2 gene was previously reported in a dog model of late onset lethal form of NCL. This variant causes exon skipping as the result of a broken exonic splicing enhancer motif (Wöhlke et al. 2011; Farias et al. 2011).

The ATP13A2 gene encodes a lysosomal transport protein that is part of the P-type superfamily of ATPases (Schultheis et al. 2004).

Pathogenic variants in ATP13A2 appear to be a rare cause of NCL. Only one NCL family with such variants has been reported to date (Bras et al. 2012).

Testing Strategy

This test provides full coverage of all coding exons of the ATP13A2 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other 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).

Clinical Sensitivity - Sequencing with CNV

Pathogenic variants in ATP13A2 appear to be a rare cause of NCL. Only one NCL family with a pathogenic ATP13A2 variant has been reported to date (Bras et al. 2012).

Indications for Test

Candidates for the ATP13A2 test are patients with a clinical diagnosis suggestive of neuronal ceroid lipofuscinosis and no pathogenic variants in the remaining NCL genes. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in ATP13A2.

Gene

Official Gene Symbol OMIM ID
ATP13A2 610513
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Ceroid Lipofuscinosis Neuronal 12 AR 606693

Citations

  • Bras J et al. 2012. Human molecular genetics. 21: 2646-50 PubMed ID: 22388936
  • De Volder AG. et al. 1990. Journal of neurology, neurosurgery, and psychiatry. 53: 1063-7 PubMed ID: 2292699
  • Dyken P.R. 1988. American journal of medical genetics. Supplement. 5: 69-84. PubMed ID: 3146331
  • Farias FH et al. Neurobiol Dis. 2011 Jun;42(3):468-74. PubMed ID: 21362476
  • Mole S.E., Williams R.E. 2013. Neuronal Ceroid-Lipofuscinoses. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, and Stephens K, editors. GeneReviews™, Seattle (WA): University of Washington, Seattle. PubMed ID: 20301601
  • Rider J.A., Rider D.L. 1988. American journal of medical genetics. Supplement. 5: 21-6. PubMed ID: 3146319
  • Schultheis PJ., Hagen TT. 2004. Biochemical and biophysical research communications. 323: 731-8. PubMed ID: 15381061
  • Schulz A. et al. 2004. Annals of neurology. 56: 342-50. PubMed ID: 15349861
  • Wöhlke A. et al. 2011. PLoS genetics. 7: e1002304. PubMed ID: 22022275
  • Williams R.E., Mole S.E. 2012. Neurology. 79: 183-91. PubMed ID: 22778232

Ordering/Specimens

Ordering Options

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.

Specimen Types

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