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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
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.
1098-3600
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
c763cce9-4b01-453d-8975-2a7390a8beaa
Greville-heygate, Stephanie
a952c82d-8775-45a5-9c60-478348fb02f2
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.
23c9ae66-c63c-4897-a5f1-38ef7c908f2f
Martin, Carol-anne
876ff752-67d8-4b75-986a-33101dabd4b5
Greene, Philip
8b823798-9efe-4959-9a2c-865fca2f6304
Marsh, Joseph A.
5799c486-06c3-4330-b70b-4975373fec90
Blyth, Moira
03468812-f3d2-45b5-aaa0-9e04ae9b2e8a
Cox, Helen
b59f11d7-0b83-4c0b-9bc0-e6a2654366b6
Donnelly, Deirdre
e5dc047a-2040-4ebc-a4fa-d3cd1edb2319
Greenhalgh, Lynn
c763cce9-4b01-453d-8975-2a7390a8beaa
Greville-heygate, Stephanie
a952c82d-8775-45a5-9c60-478348fb02f2
Harrison, Victoria
39844b8f-ebf6-40f9-a2b5-5fd8d588c672
Lachlan, Katherine
175ce889-ede8-477e-93eb-afefc1af5dda
Mckenna, Caoimhe
2723a3bb-00e1-443c-a046-393b1346998b
Quigley, Alan J.
25c29575-25fe-439f-8d20-d72f3cb966dd
Rea, Gillian
90a222ce-41e5-48f9-a58f-831899fa8de6
Robertson, Lisa
f038359c-ff35-40eb-a859-1281c1649687
Suri, Mohnish
bb44c6fb-9bfd-4bd5-a187-b245c17bbd6f
Jackson, Andrew P.
e29954ee-9a8c-4434-8e17-137cbaf721d5

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), 408-414. (doi:10.1038/s41436-020-00980-3).

Record type: Article

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.

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Accepted/In Press date: 17 September 2020
e-pub ahead of print date: 9 October 2020
Additional Information: 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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