Leukodystrophy, adult onset

Gene: LAMB1

Green List (high evidence)

Comment on mode of inheritance: There are multiple patients reported with heterozygous frameshift LAMB1 variants and an adult-onset cerebral small vessel disease with leukoencephalopathy. There is only one individual reported to date with a biallelic missense variant and an adult-onset neurodegenerative disorder (PMID: 32548278). Hence, the mode of inheritance of this gene should be changed to 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' only.

Created: 9 Oct 2026, 4:27 p.m. | Last Modified: 9 Oct 2026, 4:27 p.m.

Panel Version: 7.12

PMID: 32548278 Yasuda et al., 2020 - BIALLELIC ADULT CASE
Report of a 37-year-old Japanese woman with headache, memory loss, mild flexion of retinal vessels, and gait disturbance. She was born to consanguineous parents. Her symptoms started at 22 yrs with a migraine. Brain MRI showed a cerebral white matter lesion at age 30 years. Wechsler Adult Intelligence Scale–Third Edition indicated a full-scale IQ of 69 - borderline ID. Seq method: targeted exome seq of 115 genes. She was found to be homozygous for LAMB1: c.1378T>C, p.Cys460Arg variant. Parents confirmed het. There is only 1 het individual reported in gnomAD v4.1.2 with this variant. Authors pose that "the effect of missense mutations on the phenotype may be milder compared with that of frameshift mutations."
Functional support: PMID: 40237576 Yasuda et al., 2025 - Drosophila melanogaster model. Study found that the LAMB1 fly ortholog LanB1 gene is expressed on the surface of adult fly brains in a subset of glia cells. While human LAMB1 was not able to function in flies, in vivo overexpression and rescue experiments using analogous variants in fly LanB1 suggested that the frameshift variants behave as strong LoF alleles whereas a missense variant functions as a milder LoF allele.

MONOALLELIC ADULT CASES:
PMID: 34606115 Aloui et al., 2021 - exome data of 258 cerebral small vessel disease patients. 4 patients had het frameshift variants in LAMB1 residues 1721-1750 - predicted to escape NMD (plus P5 with a het splice variant but not much detail provided). Age at first symptom was 20-67 yrs for patients 1-4. Common phenotype was hippocampal memory defect and leukoencephalopathy.

PMID: 37063705 Morel et al., 2023 - report of 6 patients from 2 unrelated families with het end-truncating LAMB1 variations escaping NMD. Method: targeted seq of 8 cerebral small vessel disease genes. Patients were 30-80 yo at examination. The 4 patients older than 50 years presented with an amnestic syndrome of the hippocampal type (ASHT) with mild executive dysfunction and diffuse leukoencephalopathy. Significant cognitive complaints were also present in the 2 younger patients.

PMID: 39082428 Cho et al., 2024 - Cohort of 257 suspected Cerebral Small-Vessel Disease cases. P11 had a het LAMB1 variant p.Leu1730Ter. She had memory deficit and migraine with aura when she was recruited. She had transient ischemic attack at the age of 57 years, stroke at the age of 61 years, and passed away at the age of 67 years. Brain MRI taken at the age of 64 years showed extensive confluent white matter hyperintensities, and lacunar infarcts

LAMB1 is associated with AD Leukoencephalopathy without lacunae, adult-onset, OMIM:621424 & AR Leukoencephalopathy with variable cortical brain malformations and/or hydrocephalus, OMIM:615191 (OMIM accessed 9th Oct 2026).

Created: 9 Oct 2026, 4:23 p.m. | Last Modified: 9 Oct 2026, 4:23 p.m.

Panel Version: 7.12

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Leukoencephalopathy without lacunae, adult-onset, OMIM:621424; leukoencephalopathy without lacunae, adult-onset, MONDO:0980752; Leukoencephalopathy with variable cortical brain malformations and/or hydrocephalus, OMIM:615191

Publications

• 32548278
• 34606115
• 37063705
• 39082428

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