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Genetic Epilepsy

Gene: LMNB1

Amber List (moderate evidence)

LMNB1 (lamin B1)
EnsemblGeneIds (GRCh38): ENSG00000113368
EnsemblGeneIds (GRCh37): ENSG00000113368
OMIM: 150340, Gene2Phenotype
LMNB1 is in 9 panels

3 reviews

Rylee Peters (Victorian Clinical Genetics Services)

I don't know

PMID: 32910914 – Cohort of 7 individuals from 5 families harbouring mostly de novo LMNB1 variants. Seizures described in 4 individuals from 2 families with either a missense variant (p.Arg42Trp) or splice variant (c.939+1G>A) which is predicted to result in an extension of exon 5 by 6 amino-acids.

PMID: 33033404 – Supplementary material showing clinical features of 6 individuals with LMNB1 variants from the DDD study and 100kGE study; each variant was associated with microcephaly, and global developmental delay. One missense variant, p.K33E, was described as de novo in 3 individuals who also had seizures.
Created: 20 Dec 2023, 1:39 a.m. | Last Modified: 20 Dec 2023, 1:39 a.m.
Panel Version: 0.2060

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Microcephaly 26, primary, autosomal dominant (MIM#619179)

Publications

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Comment when marking as ready: Note different mechanism for LMNB1-related neurodevelopmental phenotype cf Adult-onset leukodystrophy phenotype previously associated with this gene.
Created: 18 Sep 2020, 1:18 a.m. | Last Modified: 18 Sep 2020, 1:18 a.m.
Panel Version: 0.862

Konstantinos Varvagiannis (Other)

I don't know

Cristofoli et al (2020 - PMID: 32910914) report 7 individuals (from 5 families) harboring mostly de novo LMNB1 variants.

The common phenotype consisted of primary microcephaly (7/7 ranging from -4.4 to -10 SD), DD/ID (7/7), relative short stature in most (+0.7 to -4 SD). Additional features included brain MRI abnormalities (abnormal CC in 3, simplified gyral pattern in 3, small structurally normal brain, etc), seizures (4 individuals from 2 families), limb spasticity (1/7), cortical visual impairment (in 3), feeding difficulties (5/7), scoliosis (4/7). Non-overlapping dysmorphic features were reported in some.

Variants were identified by WES or custom-designed gene panel and included 3 missense variants, 1 in-frame deletion and a splice variant. The in-frame deletion was inherited from a similarly affected parent in whom the variant occurred as a dn event. The splice SNV(NM_005573.3:c.939+1G>A) occurred in 3 sibs and was present as mosaic variant (15%) in the parent. This variant was predicted to result to extension of exon 5 by 6 amino-acids (samples were unavailable for mRNA studies).

LMNB1 encodes a B-type lamin (the other being encoded by LMNB2). A- and B- type lamins are major components of the nuclear lamina. As the authors comment, LMNB1 is expressed in almost all cell types beginning at the earliest stages of development.

Lamin-deficient mouse models support an essential role of B-type lamins in organogenesis, neuronal migration, patterning during brain development.

Functional studies performed, demonstrated impaired formation of LMNB1 nuclear lamina in LMNB1-null HeLa cells transfected with cDNAs for 3 missense variants.

Two variants (Lys33Glu/Arg42Trp) were shown to result in decreased nuclear localization with increased abundance in the cytosolic fraction. In patient derived LCLs these variants led to abnormal nuclear morphology. A missense variant in another domain (Ala152Gly - 1st coil domain) resulted also in lower abundance of lamin B1, irregular lamin A/C nuclear lamina, as well as more condensed nuclei (HeLa cells).

LMNB1 duplications or missense mutations increasing LMNB1 expression are associated with a different presentation of AD leuodystrophy. A variant previously associated with leukodystrophy (Arg29Trp) was shown to behave differently (present in the nuclear extract but not in the cytosol, lamin B1 to A/C ratio in nuclear extract was not significantly altered compared to wt as was the case for Arg42Trp, Lys33Glu).

Given the pLI score of 0.55 as well as the phenotype of individuals with deletions (not presenting microcephaly) the authors predict that a dominant-negative effect applies (rather than haploinsufficiency).

Consider inclusion in the following panels : DD/ID (green), epilepsy (amber - 4 of 7 patients belonging to 2 families), primary microcephaly (green), callosome (amber/green - 3 individuals belonging to 3 families), mendeliome (green), etc.
Sources: Literature
Created: 18 Sep 2020, 12:03 a.m.

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

Phenotypes
Global developmental delay; Intellectual disability; Microcephaly; Short stature; Seizures; Abnormality of the corpus callosum; Cortical gyral simplification; Feeding difficulties; Scoliosis

Publications

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Amber
Phenotypes
  • Global developmental delay
  • Intellectual disability
  • Microcephaly
  • Short stature
  • Seizures
  • Abnormality of the corpus callosum
  • Cortical gyral simplification
  • Feeding difficulties
  • Scoliosis
OMIM
150340
Clinvar variants
Variants in LMNB1
Penetrance
unknown
Publications
Mode of Pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Panels with this gene

History Filter Activity

18 Sep 2020, Gel status: 2

Entity classified by Genomics England curator

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Gene: lmnb1 has been classified as Amber List (Moderate Evidence).

18 Sep 2020, Gel status: 2

Set mode of pathogenicity

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Mode of pathogenicity for gene: LMNB1 was changed from Other to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

18 Sep 2020, Gel status: 2

Entity classified by Genomics England curator

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Gene: lmnb1 has been classified as Amber List (Moderate Evidence).

18 Sep 2020, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance, Set mode of pathogenicity

Konstantinos Varvagiannis (Other)

gene: LMNB1 was added gene: LMNB1 was added to Genetic Epilepsy. Sources: Literature Mode of inheritance for gene: LMNB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: LMNB1 were set to 32910914 Phenotypes for gene: LMNB1 were set to Global developmental delay; Intellectual disability; Microcephaly; Short stature; Seizures; Abnormality of the corpus callosum; Cortical gyral simplification; Feeding difficulties; Scoliosis Penetrance for gene: LMNB1 were set to unknown Mode of pathogenicity for gene: LMNB1 was set to Other Review for gene: LMNB1 was set to AMBER