David A Parry1, Carol-Anne Martin1, Philip Greene1, Joseph A Marsh1, Moira Blyth2, Helen Cox3, Deirdre Donnelly4, Lynn Greenhalgh5, Stephanie Greville-Heygate6,7, Victoria Harrison8, Katherine Lachlan7,9, Caoimhe McKenna4, Alan J Quigley10, Gillian Rea4, Lisa Robertson11, Mohnish Suri12, Andrew P Jackson13. 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. Andrew.Jackson@igmm.ed.ac.uk.
Abstract
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.
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.