Adult onset neurodegenerative disorder

Gene: CST3

I don't know

The rating of this gene has been set to Amber and the mode of inheritance set to 'MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown' following NHS Genomic Medicine Service approval.

Created: 1 Feb 2023, 12:22 p.m. | Last Modified: 1 Feb 2023, 12:22 p.m.

Panel Version: 3.49

Green List (high evidence)

Comment on list classification: There are >3 unrelated cases with Cerebral amyloid angiopathy (MIM #105150), however they were all reported with the same founder variant.

However, there are 18 patients from ten unrelated families with adult-onset leukodystrophy phenotype (not yet reported in OMIM) and with five different monoallelic variants, of which eight patients from five families were reported with cognitive decline and dementia on or before the age of 55.

Hence, there is sufficient evidence available for the promotion of this gene to green rating on the next GMS update.

Created: 14 Apr 2025, 5:23 p.m. | Last Modified: 14 Apr 2025, 5:23 p.m.

Panel Version: 7.19

PMID:38489591 reported 16 patients from eight families with a novel adult-onset leukodystrophy disorder and with one of four different stop-gain or frameshift monoallelic variants in the CST3 gene. The reported variants are c.360del, c.357+1del, c.340C>T and c.376C>T, and none of these variants are found in general population (gnomAD). Clinical and radiological features of these patients differ markedly from the previously described Icelandic cerebral amyloid angiopathy found in patients carrying p.Leu68Asn substitution in CST3. The clinical phenotype consists of recurrent episodes of hemiplegic migraine associated with transient unilateral focal deficits and slowly progressing motor symptoms and cognitive decline in mid to older adult ages. Cognitive decline and dementia were present in 11 patients from seven families, of which seven patients from four families were aged below 55.

PMID:38729262 reported two unrelated Chinese individuals with adult-onset leukodystrophy and with monoallelic CST3 variants. One patient had the previously reported c.340C>T variant, while the other had novel c.357+1G>T variant. Memory deterioration and cognitive decline has been noted in the 48-year-old female patient with the novel variant.

This gene has only been reported with Cerebral amyloid angiopathy (MIM #105150) and not yet with the adult-onset leukodystrophy phenotype in OMIM.

Created: 14 Apr 2025, 5:14 p.m. | Last Modified: 14 Apr 2025, 5:14 p.m.

Panel Version: 7.15

There are >3 unrelated cases with relevant phenotype (cerebral amyloid angiopathy) and age of onset is third or fourth decade of life. However, all these cases were identified with the same heterozygous variant in the CST3 gene (p.L68Q) and was from the same Icelandic population. There should be functional studies on this specific variant, de novo cases with this variant from other populations or existence of other variants causing the same phenotype for it to be rated green. Hence, this gene is rated AMBER.

Created: 10 Jan 2023, 6:37 p.m. | Last Modified: 10 Jan 2023, 6:43 p.m.

Panel Version: 3.47

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Cerebral amyloid angiopathy, OMIM:105150; leukodystrophy, MONDO:0019046

Publications

• 38489591
• 38729262

Review submitted on behalf of David Lynch, James Polke, Henry Houlden, Lucy Jenkins. Mode of inheritance: AD. Phenotype: Cerebral amyloid angiopathy. Evidence: MIM: 105150. Icelandic founder mutation

Created: 22 Dec 2022, 12:10 p.m. | Last Modified: 22 Dec 2022, 12:10 p.m.

Panel Version: 3.4

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

Phenotypes
Cerebral amyloid angiopathy