Neuronal Ceroid Lipofuscinosis 3 (Batten Disease) via the CLN3 c.461-280_677+382 Deletion

Summary and Pricing

Test Method

Targeted Deletion Testing via PCR
Test Code Test Copy GenesPrice Test CPT CodeGene CPT Codes Copy CPT Codes STAT
3739 CLN3$490 8147981479 Add to Order

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Turnaround Time

The great majority of tests are completed within 18 days.

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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, and 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; Vesa et al. 1995). 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 groups 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). CLN3 disease, juvenile, also known as Batten Disease or Spielmeyer-Vogt Disease, is the most common neurodegenerative disorder of childhood (Zeman 1974). It is characterized by onset between 5-10 years of age, death in the third decade of life and mild features. Progressive visual loss is usually the first manifestation followed by seizures and cognitive and motor decline. Psychotic symptoms have also been reported (Adams et al. 2010).

Genetics

Most CLNs, including CLN3, are inherited in an autosomal recessive manner. Thirteen genes have been implicated in CLNs: PPT1, TPP1, CLN3, CLN5, CLN6, MFSD8, CLN8, CTSD, DNAJC5, CTSF, ATP13A2, GRN, and KCTD7 (Mole and Williams 2013). CLN3 is caused by defects in the CLN3 gene (ICBD 1995). About 60 CLN3 pathogenic variants have been reported in various ethnic populations and include missense; nonsense; splicing; and small insertions and deletions. A 1-kb genomic deletion (c.461-280_677+382del), accounts for up to 85% of pathogenic variants in patients with CLN3 (Human Gene Mutation Database; Munroe et al. 1997). The great majority of CLN3 pathogenic variants are predicted to result in truncated proteins.

The CLN3 gene encodes a transmembrane protein that is hypothesized to be involved in membrane trafficking and several other cellular functions.

Testing Strategy

A genomic deletion of 1.02 kb in the CLN3 gene accounts for up to 85% of pathogenic variants in patients with Batten disease, also known as CLN3. This deletion is described as c.461-280_677+382del; it includes exons 8 and 9 of the gene (Munroe et al. 1997). This test involves amplification of patient DNA with specific PCR primers that flank the c.461-280_677+382del deletion. Positive control samples from patients homozygous and heterozygous for the deletion are included in this test. A healthy non-carrier is included as a negative control.

Clinical Sensitivity - Targeted Deletion

The genomic deletion of 1.02 kb in the CLN3 gene accounts for up to 85% of pathogenic variants in patients with CLN3 disease (Munroe et al. 1997). To date, only two other multi-exonic deletions were reported (Human Gene Mutation Database). They appear to be private or rare (Mole and Williams 2013).

Indications for Test

Candidates for this test are patients with a clinical diagnosis of CLN3 (Batten disease), and biological relatives of patients who are known to have the c.461-280_677+382 deletion in the CLN3 gene.

Gene

Official Gene Symbol OMIM ID
CLN3 607042
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Ceroid Lipofuscinosis Neuronal 3 AR 204200

Related Tests

Name
Autosomal Recessive Retinitis Pigmentosa Panel
Retinitis Pigmentosa (includes RPGR ORF15) Panel

Citations

  • Adams H.R. et al. 2010. Developmental Medicine and Child Neurology. 52: 637-43. PubMed ID: 20187884
  • Dyken P.R. 1988. American journal of medical genetics. Supplement. 5: 69-84. PubMed ID: 3146331
  • Human Gene Mutation Database (Bio-base).
  • 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
  • Munroe P.B. et al. 1997. American Journal of Human Genetics. 61: 310-6. PubMed ID: 9311735
  • Rider J.A., Rider D.L. 1988. American journal of medical genetics. Supplement. 5: 21-6. PubMed ID: 3146319
  • Schulz A. et al. 2004. Annals of neurology. 56: 342-50. PubMed ID: 15349861
  • The International Batten Disease Consortium (IBDC) 1995. Isolation of a novel gene underlying Batten disease, CLN3. Cell 82:949-57. PubMed ID: 7553855
  • Vesa J. et al. 1995. Nature. 376: 584-7. PubMed ID: 7637805
  • Williams R.E., Mole S.E. 2012. Neurology. 79: 183-91. PubMed ID: 22778232
  • Zeman W. 1974. Journal of Neuropathology and Experimental Neurology. 33: 1-12. PubMed ID: 4812323

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