Adult onset leukodystrophy

Gene: LAMB1

Green List (high evidence)

The rating of this gene has been updated to Green and the mode of inheritance set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal 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

PMID: 34606115 reports heterozygous end-truncated LAMB1 in a hippocampal memory defect and a leukoencephalopathy. Other publications (PMID: 32548278; 25925986;23472759;29888467),
OMIM (https://www.omim.org/entry/150240?search=LAMB1&highlight=lamb1#geneMap) Gen2Phen (https://www.ebi.ac.uk/gene2phenotype/gfd?dbID=1439) and ClinGen (https://search.clinicalgenome.org/kb/genes/HGNC:6486) all report the a bialleic mode inheritance between LAMB1 variants and disease. Based on this discrepancy, the suggested mode of inheritance has been changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.

Created: 10 Jan 2023, 4:58 p.m. | Last Modified: 10 Jan 2023, 4:58 p.m.

Panel Version: 2.44

Associated with relevant phenotype in OMIM and as strong Gen2Phen gene. At least four variants have been reported in three unrelated cases of Lissencephaly 5, (OMIM:615191).

Created: 5 Jan 2023, 5:49 p.m. | Last Modified: 5 Jan 2023, 5:49 p.m.

Panel Version: 2.38

Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.

Created: 5 Jan 2023, 5:47 p.m. | Last Modified: 5 Jan 2023, 5:47 p.m.

Panel Version: 2.38

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Review submitted on behalf of David Lynch, James Polke, Henry Houlden, Lucy Jenkins. Mode of inheritance: AD. Phenotype: Cerebral small vessel disease, with leukoencephalopathy and hippocampal memory impairment. Evidence: PMID:34606115: A significant over-representation of truncating (non-NMD) LAMB1 variants in CSVD pateints vs. controls. Four familes with 3 different frameshifts variants that escape NMD presented..

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 small vessel disease, with leukoencephalopathy and hippocampal memory impairment

Publications

• 34606115

Comment on list classification: Rating Red as currently only a single adult-onset case of leukoencephalopathy reported (PMID: 32548278). Additional cases required prior to inclusion on this panel. All other publications to date report congenital or infantile- to childhood-onset leukoencephalopathy.

Created: 7 Jun 2021, 10:06 a.m. | Last Modified: 7 Jun 2021, 10:06 a.m.

Panel Version: 1.12

Green List (high evidence)

New MOI

Mono-allelic LAMB1 variants reported in 5 families with cerebral small vessel disease. 4 are truncating frameshifts (and 2 of the families have the same frameshift), 1 is a canonical splice. All families had adult onset of symptoms ranging from 20-63yo. All has white matter hyper intensity on imaging.

Created: 4 Dec 2021, 2:47 a.m. | Last Modified: 4 Dec 2021, 2:47 a.m.

Panel Version: 1.36

Single adult female patient with onset of symptoms after 22yrs of age reported with novel homozygous missense variant (parents distantly related family), no further evidence of pathogenicity, however note two reports of cystic leukodystrophy in paediatric patients.
Sources: Literature

Created: 6 Jul 2020, 7:37 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Adult-onset leukodystrophy

Publications

• 32548278
• 34606115