Adult onset neurodegenerative disorder

Gene: GRN

The mode of inheritance of this gene has been updated to BOTH monoallelic and biallelic, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.

Created: 10 Oct 2023, 4:47 p.m. | Last Modified: 10 Oct 2023, 4:47 p.m.

Panel Version: 4.37

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Comment on mode of inheritance: Should be updated from 'monoallelic' only to 'both mono- and biallelic' at the next GMS panel update.

Created: 2 Nov 2022, 2:44 p.m. | Last Modified: 2 Nov 2022, 2:44 p.m.

Panel Version: 2.295

Association with monoallelic variants is well-established as these cause frontotemporal lobar degeneration. However, biallelic variants may also be pertinent. Biallelic variants are associated with neuronal ceroid lipofuscinosis (NCL) for which variable ages of onset have been reported. In adult-onset form of NCL, cognitive deterioration appears more prominent than in juvenile cases, and other neurological symptoms such as cerebellar ataxia are progressive.

Furthermore, Huin et al. 2020 (PMID: 31855245) identified two unrelated families with adult-onset disease who developed a neurological phenotype resembling bvFTD and parkinsonian symptoms of variable age-related severity. These individuals did not display other features typical NCL symptoms such as ataxia and seizures.

Created: 2 Nov 2022, 2:43 p.m. | Last Modified: 2 Nov 2022, 2:43 p.m.

Panel Version: 2.292

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Frontotemporal lobar degeneration with ubiquitin-positive inclusions, OMIM:607485; Aphasia, primary progressive, OMIM:607485; Ceroid lipofuscinosis, neuronal, 11, OMIM:614706

Publications

• 27021778
• 28000352
• 31855245

Comment on phenotypes: Previous phenotypes:
clinical presentation suggestive of cortico-basal/PSP syndrome;Complex parkinsonism;Frontotemporal Dementia;frontotemporal lobar degeneration with TDP43 inclusions;Clinical syndrome FTLD (Frontotemporal lobar degeneration)

Created: 29 Mar 2021, 10:03 a.m. | Last Modified: 29 Mar 2021, 10:03 a.m.

Panel Version: 2.90

Green List (high evidence)

TLD-TDP is a type of frontotemporal dementia which shows variable phenotypic expression, but most commonly presents with social, behavioral, or language deterioration, rather than memory or motor deficits. mean age at onset was 51 years.The frequency was 12.8% (5 of 39) in familial cases and 3.2% (5 of 158) in sporadic cases.

Created: 2 Sep 2019, 4:06 p.m. | Last Modified: 2 Sep 2019, 4:06 p.m.

Panel Version: 1.99

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
clinical presentation suggestive of cortico-basal/PSP syndrome; Complex parkinsonism; Frontotemporal Dementia; frontotemporal lobar degeneration with TDP43 inclusions; Clinical syndrome FTLD (Frontotemporal lobar degeneration)

Green List (high evidence)

Adult onset frontotemporal lobar degeneration.

Created: 23 Jul 2019, 3:35 p.m. | Last Modified: 23 Jul 2019, 3:35 p.m.

Panel Version: 1.72

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

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

I don't know

Review and rating from Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group. All the green and amber, except for the genes with triplet repeats, were reviewed.

Created: 2 Sep 2019, 4:46 p.m. | Last Modified: 2 Sep 2019, 4:46 p.m.

Panel Version: 1.101

Review and rating submitted by Nick Beauchamp (Sheffield Diagnostic genetics Service), on behalf of Yorkshire and North East GLH for GMS Neurology specialist test group.

Created: 23 Jul 2019, 3:51 p.m. | Last Modified: 23 Jul 2019, 3:51 p.m.

Panel Version: 1.74

Review and rating submitted byJames Polke (North Bristol NHS Trust), unless specified in the review comment, on behalf of London North GLH for GMS Neurology specialist test group.

Created: 23 Apr 2019, 5:35 p.m.

Green List (high evidence)

Pathogenic splicing mutations in non-coding exon/intron boundary

Created: 23 Apr 2019, 5:31 p.m.

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