Heterozygous Lamin B1 and Lamin B2 Variants cause Primary Microcephaly and Define a Novel Laminopathy

Genomics England Research Consortium, Moira Blyth, Helen Cox, Deirdre E Donnelly, Lynn Greenhalgh, Stephanie Greville-Heygate, Victoria Harrison, Katherine Lachlan, Caoimhe McKenna, Alan Quigley, Gillian Rea, Lisa Robertson, Mohnish Suri, Andrew P Jackson

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Pages (from-to)408–414
JournalGenetics in Medicine
Volume23
Issue number2
Early online date9 Oct 2020
DOIs
Publication statusE-pub ahead of print - 9 Oct 2020

Keywords

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

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