Heterozygous lamin B1 and lamin B2 variants cause primary microcephaly and define a novel laminopathy

Genomics England Research Consortium, David A. Parry, Carol Anne Martin, Philip Greene, Joseph A. Marsh, J. C. Ambrose, P. Arumugam, E. L. Baple, M. Bleda, F. Boardman-Pretty, J. M. Boissiere, C. R. Boustred, H. Brittain, M. J. Caulfield, G. C. Chan, C. E. H. Craig, L. C. Daugherty, A. de Burca, Andrew Devereau, G. ElgarR. E. Foulger, T. Fowler, P. Furió-Tarí, A. Giess, J. M. Hackett, D. Halai, A. Hamblin, S. Henderson, J. E. Holman, T. J. B. Hubbard, K. Ibáñez, R. Jackson, L. J. Jones, D Kasperaviciute, M. Kayikci, A. Kousathanas, L. Lahnstein, K. Lawson, S. E. A. Leigh, I. U. S. Leong, F. J. Lopez, F. Maleady-Crowe, J. Mason, E. M. McDonagh, L. Moutsianas, M. Mueller, N. Murugaesu, A. C. Need, C. A. Odhams, A. Orioli, C. Patch, D. Perez-Gil, M. B. Pereira, D. Polychronopoulos, J. Pullinger, T. Rahim, A. Rendon, P. Riesgo-Ferreiro, T. Rogers, M. Ryten, K. Savage, K. Sawant, R. H. Scott, A. Siddiq, A. Sieghart, D. Smedley, K. R. Smith, S. C. Smith, A. Sosinsky, W. Spooner, H. E. Stevens, A. Stuckey, R. Sultana, M. Tanguy, E. R. A. Thomas, S. R. Thompson, C. Tregidgo, A. Tucci, E. Walsh, S. A. Watters, M. J. Welland, E. Williams, K. Witkowska, S. M. Wood, M. Zarowiecki, Moira Blyth, Helen Cox, Deirdre Donnelly, Lynn Greenhalgh, Stephanie Greville-Heygate, Victoria Harrison, Katherine Lachlan, Caoimhe McKenna, Alan J. Quigley, Gillian Rea, Lisa Robertson, Mohnish Suri, Andrew P. Jackson

Research output: Contribution to journalArticlepeer-review


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.
Original languageEnglish
Pages (from-to)408-414
Number of pages7
JournalGenetics in medicine : official journal of the American College of Medical Genetics
Issue number3
Publication statusPublished - 29 Jun 2021


  • LMNB1
  • LMNB2
  • laminopathy
  • primary microcephaly
  • neurodevelopmental disorder


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