Heterozygous lamin B1 and lamin B2 variants cause primary microcephaly and define a novel laminopathy
- Genet Med. 2021 Feb;23(2):408-414. doi: 10.1038/s41436-020-00980-3.
- 1. MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
- 2. Yorkshire Regional Genetics Service, Leeds Teaching Hospitals NHS Trust, Department of Clinical Genetics, Chapel Allerton Hospital, Leeds, UK.
- 3. West Midlands Regional Genetics Service, Birmingham Women's NHS Foundation Trust, Birmingham Women's Hospital, Edgbaston, Birmingham, UK.
- 4. Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, UK.
- 5. Liverpool Centre for Genomic Medicine, Liverpool Women's Hospital, Liverpool, UK.
- 6. Faculty of Medicine, University of Southampton, Southampton, UK.
- 7. Wessex Clinical Genetics Service, University Hospital Southampton, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
- 8. Wessex Clinical Genetics Service, Princess Anne Hospital, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
- 9. Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK.
- 10. Department of Radiology, Royal Hospital for Sick Children, Edinburgh, UK.
- 11. Department of Clinical Genetics, Aberdeen Royal Infirmary, Scotland, UK.
- 12. Clinical Genetics Service, Nottingham University Hospitals NHS Trust, City Hospital Campus, Nottingham, UK.
- 13. MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK. [email protected].
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.