Neuronal ceroid lipofuscinosis

Gene: GRN

Green List (high evidence)

The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.

Created: 6 Dec 2024, 11:38 a.m. | Last Modified: 6 Dec 2024, 11:38 a.m.

Panel Version: 2.8

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Green List (high evidence)

Comment on list classification: This gene should be promoted to Green at the next GMS panel update.

Created: 2 Nov 2022, 12:38 p.m. | Last Modified: 2 Nov 2022, 12:38 p.m.

Panel Version: 1.25

- Smith et al. 2012 (PMID: 22608501); Canafoglia et al. 2014 (PMID: 24779634) - two sibs with early-adult onset neuronal ceroid lipofuscinosis (NCL) due to a homozygous GRN variant (c.813_816del). Both presented with visual loss due to progressive retinopathy, recurrent generalized seizures and mild cerebellar ataxia. One sib also had subtle cognitive dysfunction.

- Almeida et al. 2016 (PMID: 27021778) - female NCL subject presented rapidly progressive visual loss at age 25. Examination at age 30 additionally revealed retinal dystrophy and ataxia associated with severe cerebellar atrophy. She harboured a homozygous (c.900_901dupGT) GRN variant, which was found in a heterozygous state in multiple family members who interestingly presented with signs of behavioural variant frontotemporal dementia (bvFTD), primary progressive aphasia, and Parkinsonism - as is typical for carriers of pathogenic heterozygous GRN variants.

- Faber et al. 2017 (PMID: 28000352) - female patient presented with progressive gait impairment at age 21. Clinical features include spastic ataxia with severe cerebellar atrophy, seizures, severe cognitive impairment. WES showed a homozygous variants (c.767_768insCC) in the GRN gene.

- Kamate et al. 2019 (PMID: 30922528) - 14-year old girl presented with recurrent generalized seizures from age 13. Brain MRI revealed cerebellar atrophy. She had mild wide-based gait and borderline intelligence but neurological examination was otherwise within normal limits. Genetic testing revealed a homozygous variant in the GRN gene (c.912G>A).

- Huin et al. 2020 (PMID: 31855245) - six patients from four unrelated families with homozygous GRN variants (c.709-3C>G; c.443_444del; c.768_769dup; c.1A>T). Interestingly, phenotypes varied with age of onset (ranging from 7 to 56). Childhood/juvenile-onset form is characterised by generalized tonic-clonic epilepsy, cerebellar ataxia, and retinitis pigmentosa, which are later associated with frontal cognitive dysfunction. Later onset patients (2 families) developed a less severe neurological phenotype resembling bvFTD and parkinsonian symptoms of variable age-related severity. In one family retinitis pigmentosa was the first sign that remained isolated for a long time. Authors speculate that this phenotypic variability could be attributed to hypomorphic nature of variants identified in the late-onset subjects.

Created: 2 Nov 2022, 12:37 p.m. | Last Modified: 2 Nov 2022, 12:37 p.m.

Panel Version: 1.23

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Ceroid lipofuscinosis, neuronal, 11, OMIM:614706

Publications

• 22608501
• 27021778
• 28000352
• 28404863
• 30922528
• 31855245

I don't know

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Variants in this GENE are reported as part of current diagnostic practice