Neuronal ceroid lipofuscinosis: genes and variants

Genes linked to Neuronal ceroid lipofuscinosis

• CLN3: Battenin

  It participates in lysosomal and endosomal homeostasis, membrane trafficking, and cellular lipid handling, although its complete molecular role remains unresolved. Biallelic loss-of-function variants cause juvenile neuronal ceroid lipofuscinosis, with progressive vision loss, epilepsy, cognitive decline, and motor impairment.

  19 disease-causing and 261 uncertain variants in CLN3 are linked to Neuronal ceroid lipofuscinosis.

• GRN: Progranulin

  It is secreted and proteolytically processed into granulins and has roles in lysosomal function, inflammation, neuronal survival, and tissue repair. Heterozygous loss-of-function variants cause frontotemporal dementia through progranulin haploinsufficiency, while biallelic loss causes neuronal ceroid lipofuscinosis.

  3 disease-causing and 235 uncertain variants in GRN are linked to Neuronal ceroid lipofuscinosis.

Weakly linked (only a few uncertain records): MEFV.

Where Neuronal ceroid lipofuscinosis variants cluster

• CLN3 Transmembrane (positions 152–172): 4 of 19 disease-causing changes, 4.4× more than its size predicts.
• CLN3 Cytoplasmic (positions 1–37): 4 of 19 disease-causing changes, 2.5× more than its size predicts.

Known disease-causing variants in Neuronal ceroid lipofuscinosis

Uncertain variants in Neuronal ceroid lipofuscinosis that look disease-causing

Which prediction tools work for Neuronal ceroid lipofuscinosis

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• CADD: 96 out of 100
• phyloP: 96 out of 100
• CATVariant: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 94 out of 100
• PolyPhen-2: 92 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Same protein, different disease

• Juvenile neuronal ceroid lipofuscinosis is also caused by CLN3 variants; they fall partly in the same places as the Neuronal ceroid lipofuscinosis variants (7 disease-causing).

Diseases related to Neuronal ceroid lipofuscinosis

• Retinitis pigmentosa, also linked to CLN3
• Alzheimer disease, also linked to GRN
• Frontotemporal dementia, also linked to GRN
• Juvenile neuronal ceroid lipofuscinosis, also linked to CLN3
• GRN-related frontotemporal lobar degeneration with Tdp43 inclusions, also linked to GRN
• Dementia, also linked to GRN
• Parkinsonian disorder, also linked to GRN

Frequently asked questions

Which genes are linked to Neuronal ceroid lipofuscinosis?

In CATVariant, Neuronal ceroid lipofuscinosis is linked to 2 analyzed proteins: CLN3 (Battenin) and GRN (Progranulin).

How many genetic variants are linked to Neuronal ceroid lipofuscinosis?

587 variants: 22 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 496 are of uncertain significance or have conflicting reports.

Which uncertain variants in Neuronal ceroid lipofuscinosis look disease-causing?

1 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example CLN3 G187E. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Neuronal ceroid lipofuscinosis?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.96, based on 13 disease-causing and 19 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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