Heterozygous lamin B1 and lamin B2 variants cause primary microcephaly and define a novel laminopathy David A. Parry, PhD 1 , Carol-Anne Martin, PhD, MRes 1 , Philip Greene, BSc, MA 1 , Joseph A. Marsh, PhD 1 , Genomics England Research Consortium, Moira Blyth, MBChB, DM 2 , Helen Cox, MD 3 , Deirdre Donnelly, MD 4 , Lynn Greenhalgh, MBBS, FRCP 5 , Stephanie Greville-Heygate, MBChB, MSc 6,7 , Victoria Harrison, MBChB, FRCP 8 , Katherine Lachlan, MBChB, FRCP 7,9 , Caoimhe McKenna, MBBS, MSc 4 , Alan J. Quigley, MBChB, FRCR 10 , Gillian Rea, PhD, MA 4 , Lisa Robertson, MBChB 11 , Mohnish Suri, MD, FRCP 12 and Andrew P. Jackson, MBBS, PhD 1 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 result- ing 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 micro- cephaly, 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. Genetics in Medicine (2021) 23:408–414; https://doi.org/10.1038/s41436- 020-00980-3 Key words: LMNB1; LMNB2; laminopathy; primary microce- phaly; neurodevelopmental disorder INTRODUCTION The nuclear lamina is a protein structure that lines the inner nuclear membrane and provides structural support to the nucleus. 1 Lamins are the major component of the nuclear lamina, forming a meshwork of filaments; they interact with numerous proteins and also act as a signaling hub, linking the nuclear lamina to the cytoskeleton and chromatin. Conse- quently, as well as maintaining structural integrity of the nucleus, they influence chromatin organization, DNA tran- scription, repair, and replication. 1 Vertebrate cells express two classes of lamins, A and B, grouped based on sequence homology. Lamins A and C (A- types) are splice isoforms encoded by the same gene, while the B-type lamins are the products of different genes. 1 Over the past two decades many disorders have been linked to LMNA variants, collectively termed laminopathies. Four major disease categories have been described with overlapping features: striated muscle diseases, lipodystrophy syndromes, peripheral neuropathies, and accelerated aging (segmental progeroid) disorders. 2 In contrast to LMNA, few reports have associated human disease with variants in B-type lamin genes. No pathogenic single-nucleotide variants in LMNB1 have been reported, although genomic duplications incorporating LMNB1 cause adult-onset leukodystrophy (MIM 169500). 3 For LMNB2, a homozygous missense variant in a family with progressive myoclonic epilepsy and ataxia has been described. 4 Enrichment of heterozygous LMNB2 variants in Submitted 29 June 2020; revised 14 September 2020; accepted: 17 September 2020 Published online: 9 October 2020 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. Correspondence: Andrew P. Jackson (Andrew.Jackson@igmm.ed.ac.uk) BRIEF COMMUNICATION 408 Volume 23 | Number 2 | February 2021 | GENETICS in MEDICINE