Invitae Comprehensive Neuronal Ceroid Lipofuscinoses Panel

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  • Test code: 03405
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit
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Test description

The Invitae Comprehensive Neuronal Ceroid Lipofuscinoses Panel analyzes up to 13 genes that are associated with neuronal ceroid lipofuscinosis (NCL), also known as Batten disease. This test is useful for the diagnosis of individuals in whom NCL is suspected due to abnormal laboratory findings and clinical symptoms. Genetic testing of these genes may confirm a diagnosis and help guide management decisions.

Please note, if the patient’s primary presentation symptom is epilepsy but other NCL symptoms such as visual decline, behavioral/psychiatric symptoms, motor disturbances, or others are not present, consider choosing the Invitae epilepsy panel instead, as this panel includes most NCL genes, except CLN11, CLN12, and CLN13, which are associated with adult onset forms of NCL.

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Primary panel (9 genes)

CLN2 (TPP1) CLN3 CLN5 CLN6 CLN8 CTSD KCTD7 MFSD8 PPT1

CLN3: Analysis includes the intronic variant NM_001042432.1; c.461-13G>C.
PPT1: Analysis includes the large, mostly intronic deletion NM_000310.3:c.124+1215_235-102del3627 as well as the intronic variant NM_000310.3:c.125-15T>G.

Add-on Adult-onset Neuronal Ceroid Lipofuscinoses Genes (3 genes)

Individuals under the age of 18 should undergo comprehensive pre-test genetic counseling before considering genetic testing for adult-onset forms of NCL; specifically for the GRN gene, which, along with being associated with autosomal recessive NCL, is also associated with autosomal dominant frontotemporal dementia, a progressive neurodegenerative condition with an age of onset which ranges from the 30s to 80s. For more information on genetic testing in minors, please refer to the ASHG position statement.

CTSF DNAJC5 GRN

Add-on Preliminary-evidence Gene for Neuronal Ceroid Lipofuscinoses (1 gene)

Preliminary-evidence genes currently have early evidence of a clinical association with the specific disease covered by this test. Some clinicians may wish to include genes which do not currently have a definitive clinical association, but which may prove to be clinically significant in the future. These genes can be added at no additional charge. Visit our Preliminary-evidence genes page to learn more.

ATP13A2

  • neuronal ceriod lipofuscinosis – also known as Batten disease
    • adult neuronal ceroid lipofuscinosis
    • congenital neuronal ceroid lipofuscinosis
    • CLN2 disease
    • infantile neuronal ceroid lipofuscinosis
    • juvenile neuronal ceroid lipofuscinosis
    • late-infantile neuronal ceroid lipofuscinosis
Gene Disorder
PPT1 CLN1
TPP1 CLN2
CLN3 CLN3
DNAJC5 CLN4B
CLN5 CLN5
CLN6 CLN6
MFSD8 CLN7
CLN8 CLN8
CTSD CLN10
GRN CLN11
CTSF CLN13
KCTD7 CLN14
ATP13A2* CLN12

*preliminary-evidence gene

The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative lysosomal storage disorders that result in defective sphingolipid synthesis and the accumulation of autofluorescent ceroid lipopigments in the central nervous system. Symptom onset ranges from birth to adulthood. NCLs may be classified according to age of onset: congenital (before or around birth), infantile (6–24 months), late-infantile (2–8 years), juvenile (4–10 years), and adult (15+ years). Depending on the underlying gene, NCL can cause one or several clinical subtypes.

The NCLs are characterized by progressive psychomotor and cognitive decline, seizures, epilepsy, and early death. Most types of NCL, except for the adult form and Northern epilepsy, are associated with visual impairment that often progresses to blindness. In some NCLs, developmental delay, speech delay, ataxia, cerebellar and cerebral atrophy, hand stereotypies, sleep disturbances, behavioral/psychiatric disturbances, or additional brain MRI findings may develop. The age of onset and rate of disease progression are dependent on the underlying genetic condition.

Electron microscopy on lymphocytes or tissue biopsy may reveal characteristic histological findings among individuals with NCL. Individuals with CLN3, and some with CLN8, will have vacuolated lymphocytes. Depending on the underlying genetic condition, individuals with NCL can also have granular osmiophilic deposits (GROD), predominantly curvilinear profiles (CVB), fingerprint profiles (FP), or a mixture of all three deposit types upon electron microscopy analysis of tissues; however, invasive procedures are needed to collect tissue specimens for such analysis. Individuals with TPP1-, PPT1-, and CTSD-related CLN will have low enzyme activity in leukocytes or fibroblasts of the respective enzyme. Due to the overlapping nature of these disorders and the lack of enzyme analyses available for all clinical subtypes, panel testing of NCLs using molecular approaches can reduce the time to diagnosis in many individuals.

Although therapy is generally palliative or symptomatic, determining the underlying genetic cause can help guide management options: Some seizure medications and other types of medications may be contraindicated in these individuals. In addition, some of the NCLs currently have therapies in clinical trials. For more information, see clinicaltrials.gov.

The clinical sensitivity of this test is dependent on the individual’s underlying genetic condition. This panel tests all of the known genetic causes of congenital, infantile, late infantile, juvenile, and adult NCL.

All forms of NCL tested in this panel are inherited in an autosomal recessive manner except for DNAJC5-related NCL, which is inherited in an autosomal dominant pattern.

The NCLs have an estimated prevalence of 1 in 112,000–670,000.

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
ATP13A2 NM_022089.3
CLN2 (TPP1) NM_000391.3
CLN3* NM_001042432.1
CLN5 NM_006493.2
CLN6 NM_017882.2
CLN8 NM_018941.3
CTSD NM_001909.4
CTSF NM_003793.3
DNAJC5 NM_025219.2
GRN NM_002087.3
KCTD7 NM_153033.4
MFSD8 NM_152778.2
PPT1* NM_000310.3

CLN3: Analysis includes the intronic variant NM_001042432.1; c.461-13G>C.
PPT1: Analysis includes the large, mostly intronic deletion NM_000310.3:c.124+1215_235-102del3627 as well as the intronic variant NM_000310.3:c.125-15T>G.