2. Academic Validation
  3. Heterozygous lamin B1 and lamin B2 variants cause primary microcephaly and define a novel laminopathy

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.
David A Parry 1,  Carol-Anne Martin 1,  Philip Greene 1,  Joseph A Marsh 1,  Genomics England Research Consortium,  Moira Blyth 2,  Helen Cox 3,  Deirdre Donnelly 4,  Lynn Greenhalgh 5,  Stephanie Greville-Heygate 6 7,  Victoria Harrison 8,  Katherine Lachlan 7 9,  Caoimhe McKenna 4,  Alan J Quigley 10,  Gillian Rea 4,  Lisa Robertson 11,  Mohnish Suri 12,  Andrew P Jackson 13
Affiliations

Affiliations

  • 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.
PMID: 33033404 DOI: 10.1038/s41436-020-00980-3
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.

Keywords

LMNB1; LMNB2; laminopathy; neurodevelopmental disorder; primary microcephaly.

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