| Description: |
Purpose: lamins 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. Methods: we investigated exome and genome sequencing from the Deciphering Developmental Disorders Study and the 100,000 Genomes Project to identify novel microcephaly genes. Results: starting 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. Conclusion: we 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. |
| Relation: |
https://eprints.soton.ac.uk/450511/1/s41436_020_00980_3.pdf; Parry, David A., Martin, Carol-anne, Greene, Philip, Marsh, Joseph A., Blyth, Moira, Cox, Helen, Donnelly, Deirdre, Greenhalgh, Lynn, Greville-heygate, Stephanie, Harrison, Victoria, Lachlan, Katherine, Mckenna, Caoimhe, Quigley, Alan J., Rea, Gillian, Robertson, Lisa, Suri, Mohnish and Jackson, Andrew P. (2020) Heterozygous lamin B1 and lamin B2 variants cause primary microcephaly and define a novel laminopathy. Genetics in Medicine, 23 (2), 408-414. (doi:10.1038/s41436-020-00980-3 ). |