Neurodegenerative disorders, 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', with expert review to ensure GMS agreement on this MOI 'demotion'.

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

Panel Version: 9.25

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, 3:52 p.m. | Last Modified: 9 Oct 2026, 4:18 p.m.

Panel Version: 9.25

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 'BIALLELIC, autosomal or pseudoautosomal' 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 classification: Sufficient evidence to promote this gene to Green at the next GMS panel update. >3 unrelated cases including relevant phenotype (lissencephaly).

This gene has been associated with relevant phenotypes in both OMIM and G2P. OMIM records that onset of this disorder is in the first decade (range infancy to later childhood).

Created: 4 Jan 2023, 10:33 p.m. | Last Modified: 4 Jan 2023, 10:33 p.m.

Panel Version: 3.28

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Lissencephaly 5, OMIM:615191

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, 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 small vessel disease, with leukoencephalopathy and hippocampal memory impairment

Publications

• 34606115