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

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. We investigated exome and genome sequencing from the Deciphering Developmental Disorders Study and the 100,000 Genomes Project to identify novel microcephaly genes. 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. 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.

Citation

David A Parry, Carol-Anne Martin, Philip Greene, Joseph A Marsh, Genomics England Research Consortium, 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. Heterozygous lamin B1 and lamin B2 variants cause primary microcephaly and define a novel laminopathy. Genetics in medicine : official journal of the American College of Medical Genetics. 2021 Feb;23(2):408-414

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PMID: 33033404

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