Neuronal Ceroid Lipofuscinoses (Batten Disease) Panel

The neuronal ceroid lipofuscinoses (NCLs) are inherited neurodegenerative lysosomal storage disorders caused by the accumulation of autofluorescent material 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 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 on the age of onset of symptoms and the disease-causing gene has been recently developed, which classifies NCLs into the following thirteen subtypes (Williams and Mole 2012):

Nomenclature

The causative gene for the CLN9 phenotype has not yet been identified (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 mutations in CLN3.

Each subtye is further divided into subgroups based on the age of onset of symptoms. Subclassifications may be found in the individual gene test descriptions.

Thirteen genes have been implicated in neuronal ceroid lipofuscinoses (NCLs): PPT1, TPP1, CLN3, CLN5, CLN6, MFSD8, CLN8, CTSD, DNAJC5, CTSF, ATP13A2, GRN, and KCTD7 (reviewed in Mole and Williams 2013).

Most NCLs are inherited in an autosomal recessive manner. Autosomal dominant inheritance is documented in several families with a clinical diagnosis of CLN4. Only a subset of these families have pathogenic variants in the DNAJC5 gene, suggesting genetic heterogeneity in the autosomal dominant form of the disease (Noskova et al. 2011).

Over 400 pathogenic variants have been reported in various ethnic and geographical populations such as Northern European, Chinese, Asian Indian, Hispanic, Pakistani, South American, Italian, Israeli, German, and Arabic. Pathogenic variants include missense; nonsense; splicing; small insertions or deletions, indels and large deletions (Human Gene Mutation Database).

The PPT1, TTP1, and CTSD genes encode lysosomal enzymes. The remaining ten genes encode transmembrane proteins that localize to the endoplasmic reticulum, the endosomal or lysosomal compartments. Although the functions of some of the encoded proteins remain unknown at this time, it has been speculated that all thirteen proteins are involved in neuroprotective pathways (Bennett and Rakheja 2013).

Molecular genetic testing of the neuronal ceroid lipofuscinoses: The percentage refers to the proportion of patients with various CLNs shown to have pathogenic variants in the corresponding genes. For CLN1, CLN2 and CLN10, patients included in the studies have deficient enzyme activities in the PPT1, TPP1, and CTSD enzymes, respectively. For the remaining subtypes, patients included in the studies met the diagnostic criteria of NCL (Mole and Williams 2013).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes 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 coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).