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Heterozygous lamin B1 and lamin B2 variants cause primary microcephaly and define a novel laminopathy
- Source :
- Genetics in Medicine, Blyth, M, Cox, H, Donnelly, D E, Greenhalgh, L, Greville-Heygate, S, Harrison, V, Lachlan, K, McKenna, C, Quigley, A, Rea, G, Robertson, L & Suri, M & Jackson, A P 2020, ' Heterozygous Lamin B1 and Lamin B2 Variants cause Primary Microcephaly and Define a Novel Laminopathy ', Genetics in Medicine, vol. 23, no. 2, pp. 408–414 . https://doi.org/10.1038/s41436-020-00980-3
- Publication Year :
- 2021
-
Abstract
- PurposeLamins are the major component of nuclear lamina, maintaining structural integrity of the nucleus. Lamin A/C variants are well established to cause a spectrum of disorders ranging from myopathies to progeria, termed laminopathies. Phenotypes resulting from variants in LMNB1 and LMNB2 have been much less clearly defined.MethodsWe investigated exome and genome sequencing from the Deciphering Developmental Disorders Study and the 100,000 Genomes Project to identify novel microcephaly genes.ResultsStarting from a cohort of patients with extreme microcephaly, 13 individuals with heterozygous variants in the two human B-type lamins were identified. Recurrent variants were established to be de novo in nine cases and shown to affect highly conserved residues within the lamin ɑ-helical rod domain, likely disrupting interactions required for higher-order assembly of lamin filaments.ConclusionWe identify dominant pathogenic variants in LMNB1 and LMNB2 as a genetic cause of primary microcephaly, implicating a major structural component of the nuclear envelope in its etiology and defining a new form of laminopathy. The distinct nature of this lamin B–associated phenotype highlights the strikingly different developmental requirements for lamin paralogs and suggests a novel mechanism for primary microcephaly warranting future investigation.
- Subjects :
- 0301 basic medicine
Microcephaly
Laminopathy
laminopathy
Biology
Brief Communication
Genome
03 medical and health sciences
0302 clinical medicine
medicine
Humans
Exome
Genetics (clinical)
Genetics
Progeria
Lamin Type B
primary microcephaly
Laminopathies
medicine.disease
Phenotype
neurodevelopmental disorder
030104 developmental biology
LMNB1
LMNB2
Nuclear lamina
030217 neurology & neurosurgery
Lamin
Subjects
Details
- ISSN :
- 10983600
- Database :
- OpenAIRE
- Journal :
- Genetics in Medicine
- Accession number :
- edsair.doi.dedup.....b7c3afeb46142409f18e86e168fe778a
- Full Text :
- https://doi.org/10.1038/s41436-020-00980-3