Adult onset leukodystrophy
Gene: LAMB1
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)Map), 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
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
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: LiteratureCreated: 6 Jul 2020, 7:37 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Adult-onset leukodystrophy
Publications
Tag Q1_23_promote_green was removed from gene: LAMB1. Tag Q1_23_MOI was removed from gene: LAMB1. Tag Q1_23_NHS_review was removed from gene: LAMB1.
Source Expert Review Green was added to LAMB1. Source NHS GMS was added to LAMB1. Mode of inheritance for gene LAMB1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Tag Q1_23_MOI tag was added to gene: LAMB1.
Publications for gene: LAMB1 were set to 32548278; 34606115; 23472759; 25925986
Publications for gene: LAMB1 were set to 32548278; 34606115
Gene: lamb1 has been classified as Amber List (Moderate Evidence).
Tag Q1_23_promote_green tag was added to gene: LAMB1. Tag Q1_23_NHS_review tag was added to gene: LAMB1.
Phenotypes for gene: LAMB1 were changed from Retinal Vascular Abnormality; mild intellectual disability; white matter lesions; lower limb spasticity to Lissencephaly 5, OMIM:615191; cobblestone lissencephaly without muscular or ocular involvement, MONDO:0014077
Publications for gene: LAMB1 were set to 32548278
Gene: lamb1 has been classified as Red List (Low Evidence).
gene: LAMB1 was added gene: LAMB1 was added to White matter disorders - adult onset. Sources: Literature Mode of inheritance for gene: LAMB1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LAMB1 were set to 32548278 Phenotypes for gene: LAMB1 were set to Retinal Vascular Abnormality; mild intellectual disability; white matter lesions; lower limb spasticity Review for gene: LAMB1 was set to RED