Adult onset leukodystrophy

Gene: CST3

Green List (high evidence)

Comment on list classification: There are ten unrelated families reported with a novel adult-onset leukodystrophy disorder. Hence, this gene can be promoted to green rating in the next GMS update.

Created: 14 Apr 2025, 4:54 p.m. | Last Modified: 14 Apr 2025, 4:54 p.m.

Panel Version: 5.8

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.

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.

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, 4:51 p.m. | Last Modified: 14 Apr 2025, 4:51 p.m.

Panel Version: 5.4

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
leukodystrophy, MONDO:0019046

Publications

• 38489591
• 38729262

Green List (high evidence)

Significant evidence in at least 8 families for a leukodystrophy phenotype in adults without amyloid angiopathy

Created: 18 Mar 2025, 2:04 p.m. | Last Modified: 18 Mar 2025, 2:04 p.m.

Panel Version: 5.4

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
leukodystrophy without amyloid angiopathy

Publications

• PMID: 38489591, PMID: 38729262

I don't know

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

Created: 30 Jan 2023, 5:56 p.m. | Last Modified: 30 Jan 2023, 5:56 p.m.

Panel Version: 2.46

Associated with Cerebral amyloid angiopathy, OMIM:105150, but not associated with a phenotype in Gen2Phen. A single founder variant (NM_000099.4(CST3):c.281T>A (p.Leu94Gln)) has been associated OMIM:105150 in the Icelandic population (PMIDs: 3495457; 1352269; 8108423).

Created: 5 Jan 2023, 11:04 a.m. | Last Modified: 5 Jan 2023, 11:04 a.m.

Panel Version: 2.13

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, 2:01 p.m. | Last Modified: 22 Dec 2022, 2:01 p.m.

Panel Version: 2.3

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

Phenotypes
Cerebral amyloid angiopathy