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
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.
408-414
Parry, David A.
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Martin, Carol-anne
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Greene, Philip
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Marsh, Joseph A.
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Blyth, Moira
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Cox, Helen
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Donnelly, Deirdre
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Greenhalgh, Lynn
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Greville-heygate, Stephanie
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Harrison, Victoria
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Lachlan, Katherine
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Mckenna, Caoimhe
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Quigley, Alan J.
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Rea, Gillian
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Robertson, Lisa
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Suri, Mohnish
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Jackson, Andrew P.
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Parry, David A.
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Martin, Carol-anne
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Greene, Philip
8b823798-9efe-4959-9a2c-865fca2f6304
Marsh, Joseph A.
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Blyth, Moira
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Cox, Helen
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Donnelly, Deirdre
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Greenhalgh, Lynn
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Greville-heygate, Stephanie
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Harrison, Victoria
39844b8f-ebf6-40f9-a2b5-5fd8d588c672
Lachlan, Katherine
175ce889-ede8-477e-93eb-afefc1af5dda
Mckenna, Caoimhe
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Quigley, Alan J.
25c29575-25fe-439f-8d20-d72f3cb966dd
Rea, Gillian
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Robertson, Lisa
f038359c-ff35-40eb-a859-1281c1649687
Suri, Mohnish
bb44c6fb-9bfd-4bd5-a187-b245c17bbd6f
Jackson, Andrew P.
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Parry, David A., Martin, Carol-anne, Greene, Philip, Marsh, Joseph A., Blyth, Moira, Cox, Helen, Donnelly, Deirdre, Greenhalgh, Lynn, Greville-heygate, Stephanie, Harrison, Victoria, Lachlan, Katherine, Mckenna, Caoimhe, Quigley, Alan J., Rea, Gillian, Robertson, Lisa, Suri, Mohnish and Jackson, Andrew P.
(2020)
Heterozygous lamin B1 and lamin B2 variants cause primary microcephaly and define a novel laminopathy.
Genetics in Medicine, 23 (2), .
(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.
Text
s41436-020-00980-3
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Accepted/In Press date: 17 September 2020
e-pub ahead of print date: 9 October 2020
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Acknowledgements
We thank the families for their participation, Katya Lyulcheva-Bennett and Margaret MacDonald for assistance with clinical case characterization, Laura Murphy and IGMM imaging core for support with image analysis, and Andrea Robertson for technical assistance. Work was supported by the European Union’s Horizon 2020 research and innovation program European Research Council (ERC) Advanced Grant (grant agreement 788093); and by Medical Research Council (MRC) Unit core grant (U127580972). J.A.M., MRC Career Development Award (MR/M02122X/1) and Lister Institute Research Prize Fellowship; S.G.-H. Health Education England Genomics Education Programme research fellowship. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003). This study makes use of DECIPHER (http://decipher.sanger.ac.uk), funded by Wellcome. See Nature PMID: 25533962 or www.ddduk.org/access.html for full acknowledgement. This research was also made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK, and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support.
Identifiers
Local EPrints ID: 450511
URI: http://eprints.soton.ac.uk/id/eprint/450511
ISSN: 1098-3600
PURE UUID: 229f7629-5cd2-416b-829d-bf28367e637f
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Date deposited: 02 Aug 2021 16:30
Last modified: 16 Mar 2024 13:05
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Contributors
Author:
David A. Parry
Author:
Carol-anne Martin
Author:
Philip Greene
Author:
Joseph A. Marsh
Author:
Moira Blyth
Author:
Helen Cox
Author:
Deirdre Donnelly
Author:
Lynn Greenhalgh
Author:
Stephanie Greville-heygate
Author:
Victoria Harrison
Author:
Katherine Lachlan
Author:
Caoimhe Mckenna
Author:
Alan J. Quigley
Author:
Gillian Rea
Author:
Lisa Robertson
Author:
Mohnish Suri
Author:
Andrew P. Jackson
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