Neuronal Ceroid Lipofuscinosis 6 via the CLN6 Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
4125 CLN6 81479 81479,81479 $640 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
4125CLN681479 81479 $640 Order Options and Pricing

Pricing Comments

This test is also offered via our exome backbone with CNV detection (click here). The exome-based test may be higher priced, but permits reflex to the entire exome or to any other set of clinically relevant genes.

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

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

The neuronal ceroid lipofuscinoses 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; Bennett and Rakheja, 2013). 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; Vesa et al. 1995). NCLs are clinically and genetically heterogeneous. A nomenclature 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).

CLN6 was previously further divided into a juvenile and late infantile type and an adult type known as Lake-Cavanagh Disease and Kufs Disease type A, respectively. It is now recognized that the age of onset for CLN6 is wide, ranging between 18 months and 51 years. Disease progression is slower compared to that of CLN2 (Kousi et al. 2012).

Presenting features of CLN6 include seizures, motor difficulties, myoclonic jerks, speech impairment, ataxia and mental decline. Vision impairment appears later in life (Mole et al. 2005). Electrophysiological findings include electroretinogram and electroencephalogram attenuation, cortical hyperexcitability, and enlarged somatosensory evoked potentials (Canafoglia et al. 2015).

Genetics

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

CLN6 is caused by pathogenic variants in the CLN6 gene (Gao et al. 2002; Wheeler et al. 2002). Over 60 variants have been reported in various ethnic populations. The vast majority are missense. Other types include nonsense, splicing, and small insertions or deletions. Only one large pathogenic deletion was reported in patients from Saudi Arabia (Al-Muhaizea et al. 2009).

The CLN6 gene encodes a membrane protein localized in the endoplasmic reticulum (Sharp et al. 2003; Heine et al. 2007). It is postulated that the encoded protein mediates the transport of proteins or lipids that are essential for lysosomal function and acidification (Mole et al. 2004). However, its precise function is unknown at this time.

Clinical Sensitivity - Sequencing with CNV PG-Select

Pathogenic variants in CLN6 were identified in about 14% and 17% of clinically diagnosed NCL cases from Newfoundland and Italy, respectively (Moore et al. 2008; Santorelli et al. 2013).

Testing Strategy

This test provides full coverage of all coding exons of the CLN6 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

Indications for Test

Candidates for this test are patients with a clinical diagnosis suggestive of neuronal ceroid lipofuscinosis, regardless to the age of onset of symptoms. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in CLN6.

Gene

Official Gene Symbol OMIM ID
CLN6 606725
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Test

Name
Neuronal Ceroid Lipofuscinoses (Batten Disease) Panel

Citations

  • Al-Muhaizea MA, Al-Hassnan ZN, Chedrawi A. 2009. Variant Late Infantile Neuronal Ceroid Lipofuscinosis (CLN6 Gene) in Saudi Arabia. Pediatric Neurology 41: 74–76. PubMed ID: 19520283
  • Bennett MJ, Rakheja D. 2013. The neuronal ceroid-lipofuscinoses: The Neuronal Ceroid-Lipofuscinoses. Developmental Disabilities Research Reviews 17: 254–259. PubMed ID: 23798013
  • Canafoglia L, Gilioli I, Invernizzi F, Sofia V, Fugnanesi V, Morbin M, Chiapparini L, Granata T, Binelli S, Scaioli V, Garavaglia B, Nardocci N, Berkovic SF, Franceschetti S. 2015. Electroclinical spectrum of the neuronal ceroid lipofuscinoses associated with CLN6 mutations. Neurology 10.1212/WNL.0000000000001784. PubMed ID: 26115733
  • Dyken PR, Opitz JM, Reynolds JF, Pullarkat RK. 1988. Reconsideration of the classification of the neuronal ceroid-lipofuscinoses. American Journal of Medical Genetics 31: 69–84. PubMed ID: 3146331
  • Gao H, Boustany R-MN, Espinola JA, Cotman SL, Srinidhi L, Antonellis KA, Gillis T, Qin X, Liu S, Donahue LR, Bronson RT, Faust JR, Stout D, Haines JL, Lerner TJ, MacDonald ME. 2002. Mutations in a Novel CLN6-Encoded Transmembrane Protein Cause Variant Neuronal Ceroid Lipofuscinosis in Man and Mouse. Am J Hum Genet 70: 324–335. PubMed ID: 11791207
  • Heine C, Quitsch A, Storch S, Martin Y, Lonka L, Lehesjoki A-E, Mole SE, Braulke T. 2007. Topology and endoplasmic reticulum retention signals of the lysosomal storage disease-related membrane protein CLN6. Mol. Membr. Biol. 24: 74–87. PubMed ID: 17453415
  • Kousi M, Lehesjoki A-E, Mole SE. 2012. Update of the mutation spectrum and clinical correlations of over 360 mutations in eight genes that underlie the neuronal ceroid lipofuscinoses. Human Mutation 33: 42–63. PubMed ID: 21990111
  • 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
  • Mole SE, Michaux G, Codlin S, Wheeler RB, Sharp JD, Cutler DF. 2004. CLN6, which is associated with a lysosomal storage disease, is an endoplasmic reticulum protein. Exp. Cell Res. 298: 399–406. PubMed ID: 15265688
  • Mole SE, Williams RE, Goebel HH. 2005. Correlations between genotype, ultrastructural morphology and clinical phenotype in the neuronal ceroid lipofuscinoses. Neurogenetics 6: 107–126. PubMed ID: 15965709
  • Moore SJ, Buckley DJ, MacMillan A, Marshall HD, Steele L, Ray PN, Nawaz Z, Baskin B, Frecker M, Carr SM, Ives E, Parfrey PS. 2008. The clinical and genetic epidemiology of neuronal ceroid lipofuscinosis in Newfoundland. Clin. Genet. 74: 213–222. PubMed ID: 18684116
  • Rider J.A., Rider D.L. 1988. American journal of medical genetics. Supplement. 5: 21-6. PubMed ID: 3146319
  • Santorelli FM. et al. 2013. Orphanet journal of rare diseases. 8: 19. PubMed ID: 23374165
  • Schulz A. et al. 2004. Annals of neurology. 56: 342-50. PubMed ID: 15349861
  • Sharp JD, Wheeler RB, Parker KA, Gardiner RM, Williams RE, Mole SE. 2003. Spectrum of CLN6 mutations in variant late infantile neuronal ceroid lipofuscinosis. Hum. Mutat. 22: 35–42. PubMed ID: 12815591
  • Vesa J, Hellsten E, Verkruyse LA, Camp LA, Rapola J, Santavuori P, Hofmann SL, Peltonen L. 1995. Mutations in the palmitoyl protein thioesterase gene causing infantile neuronal ceroid lipofuscinosis. Nature 376:584-587. PubMed ID: 7637805
  • Wheeler RB, Sharp JD, Schultz RA, Joslin JM, Williams RE, Mole SE. 2002. The Gene Mutated in Variant Late-Infantile Neuronal Ceroid Lipofuscinosis (CLN6) and in nclf Mutant Mice Encodes a Novel Predicted Transmembrane Protein. Am J Hum Genet 70: 537–542. PubMed ID: 11727201
  • Williams R.E., Mole S.E. 2012. Neurology. 79: 183-91. PubMed ID: 22778232

Ordering/Specimens

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