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

Genomics England Research Consortium; David A. Parry; Carol Anne Martin; Philip Greene; Joseph A. Marsh; J. C. Ambrose; P. Arumugam; E. L. Baple; M. Bleda; F. Boardman-Pretty; J. M. Boissiere; C. R. Boustred; H. Brittain; M. J. Caulfield; G. C. Chan; C. E. H. Craig; L. C. Daugherty; A. de Burca; Andrew Devereau; G. Elgar; R. E. Foulger; T. Fowler; P. Furió-Tarí; A. Giess; J. M. Hackett; D. Halai; A. Hamblin; S. Henderson; J. E. Holman; T. J. B. Hubbard; K. Ibáñez; R. Jackson; L. J. Jones; D Kasperaviciute; M. Kayikci; A. Kousathanas; L. Lahnstein; K. Lawson; S. E. A. Leigh; I. U. S. Leong; F. J. Lopez; F. Maleady-Crowe; J. Mason; E. M. McDonagh; L. Moutsianas; M. Mueller; N. Murugaesu; A. C. Need; C. A. Odhams; A. Orioli; C. Patch; D. Perez-Gil; M. B. Pereira; D. Polychronopoulos; J. Pullinger; T. Rahim; A. Rendon; P. Riesgo-Ferreiro; T. Rogers; M. Ryten; K. Savage; K. Sawant; R. H. Scott; A. Siddiq; A. Sieghart; D. Smedley; K. R. Smith; S. C. Smith; A. Sosinsky; W. Spooner; H. E. Stevens; A. Stuckey; R. Sultana; M. Tanguy; E. R. A. Thomas; S. R. Thompson; C. Tregidgo; A. Tucci; E. Walsh; S. A. Watters; M. J. Welland; E. Williams; K. Witkowska; S. M. Wood; M. Zarowiecki; 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

doi:10.1038/s41436-020-00980-3

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

Genomics England Research Consortium, David A. Parry, Carol Anne Martin, Philip Greene, Joseph A. Marsh, J. C. Ambrose, P. Arumugam, E. L. Baple, M. Bleda, F. Boardman-Pretty, J. M. Boissiere, C. R. Boustred, H. Brittain, M. J. Caulfield, G. C. Chan, C. E. H. Craig, L. C. Daugherty, A. de Burca, Andrew Devereau, G. ElgarR. E. Foulger, T. Fowler, P. Furió-Tarí, A. Giess, J. M. Hackett, D. Halai, A. Hamblin, S. Henderson, J. E. Holman, T. J. B. Hubbard, K. Ibáñez, R. Jackson, L. J. Jones, D Kasperaviciute, M. Kayikci, A. Kousathanas, L. Lahnstein, K. Lawson, S. E. A. Leigh, I. U. S. Leong, F. J. Lopez, F. Maleady-Crowe, J. Mason, E. M. McDonagh, L. Moutsianas, M. Mueller, N. Murugaesu, A. C. Need, C. A. Odhams, A. Orioli, C. Patch, D. Perez-Gil, M. B. Pereira, D. Polychronopoulos, J. Pullinger, T. Rahim, A. Rendon, P. Riesgo-Ferreiro, T. Rogers, M. Ryten, K. Savage, K. Sawant, R. H. Scott, A. Siddiq, A. Sieghart, D. Smedley, K. R. Smith, S. C. Smith, A. Sosinsky, W. Spooner, H. E. Stevens, A. Stuckey, R. Sultana, M. Tanguy, E. R. A. Thomas, S. R. Thompson, C. Tregidgo, A. Tucci, E. Walsh, S. A. Watters, M. J. Welland, E. Williams, K. Witkowska, S. M. Wood, M. Zarowiecki, 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

Research output: Contribution to journal › Article › peer-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 language	English
Pages (from-to)	408-414
Number of pages	7
Journal	Genetics in medicine : official journal of the American College of Medical Genetics
Volume	23
Issue number	3
DOIs	https://doi.org/10.1038/s41436-020-00980-3
Publication status	Published - 29 Jun 2021

Keywords

LMNB1
LMNB2
laminopathy
primary microcephaly
neurodevelopmental disorder

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10.1038/s41436-020-00980-3

Cite this

Genomics England Research Consortium, Parry, D. A., Martin, C. A., Greene, P., Marsh, J. A., Ambrose, J. C., Arumugam, P., Baple, E. L., Bleda, M., Boardman-Pretty, F., Boissiere, J. M., Boustred, C. R., Brittain, H., Caulfield, M. J., Chan, G. C., Craig, C. E. H., Daugherty, L. C., de Burca, A., Devereau, A., ... Jackson, A. P. (2021). 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, 23(3), 408-414. https://doi.org/10.1038/s41436-020-00980-3

@article{bbd59f9a70094d8e93d75b67d5b9b1f0,

title = "Heterozygous lamin B1 and lamin B2 variants cause primary microcephaly and define a novel laminopathy",

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.",

keywords = "LMNB1, LMNB2, laminopathy, primary microcephaly, neurodevelopmental disorder",

author = "{Genomics England Research Consortium} and Parry, {David A.} and Martin, {Carol Anne} and Philip Greene and Marsh, {Joseph A.} and Ambrose, {J. C.} and P. Arumugam and Baple, {E. L.} and M. Bleda and F. Boardman-Pretty and Boissiere, {J. M.} and Boustred, {C. R.} and H. Brittain and Caulfield, {M. J.} and Chan, {G. C.} and Craig, {C. E. H.} and Daugherty, {L. C.} and {de Burca}, A. and Andrew Devereau and G. Elgar and Foulger, {R. E.} and T. Fowler and P. Furi{\'o}-Tar{\'i} and A. Giess and Hackett, {J. M.} and D. Halai and A. Hamblin and S. Henderson and Holman, {J. E.} and Hubbard, {T. J. B.} and K. Ib{\'a}{\~n}ez and R. Jackson and Jones, {L. J.} and D Kasperaviciute and M. Kayikci and A. Kousathanas and L. Lahnstein and K. Lawson and Leigh, {S. E. A.} and Leong, {I. U. S.} and Lopez, {F. J.} and F. Maleady-Crowe and J. Mason and McDonagh, {E. M.} and L. Moutsianas and M. Mueller and N. Murugaesu and Need, {A. C.} and Odhams, {C. A.} and A. Orioli and C. Patch and D. Perez-Gil and Pereira, {M. B.} and D. Polychronopoulos and J. Pullinger and T. Rahim and A. Rendon and P. Riesgo-Ferreiro and T. Rogers and M. Ryten and K. Savage and K. Sawant and Scott, {R. H.} and A. Siddiq and A. Sieghart and D. Smedley and Smith, {K. R.} and Smith, {S. C.} and A. Sosinsky and W. Spooner and Stevens, {H. E.} and A. Stuckey and R. Sultana and M. Tanguy and Thomas, {E. R. A.} and Thompson, {S. R.} and C. Tregidgo and A. Tucci and E. Walsh and Watters, {S. A.} and Welland, {M. J.} and E. Williams and K. Witkowska and Wood, {S. M.} and M. Zarowiecki and Moira Blyth and Helen Cox and Deirdre Donnelly and Lynn Greenhalgh and Stephanie Greville-Heygate and Victoria Harrison and Katherine Lachlan and Caoimhe McKenna and Quigley, {Alan J.} and Gillian Rea and Lisa Robertson and Mohnish Suri and Jackson, {Andrew P.}",

year = "2021",

month = jun,

day = "29",

doi = "10.1038/s41436-020-00980-3",

language = "English",

volume = "23",

pages = "408--414",

journal = "Genetics in medicine : official journal of the American College of Medical Genetics",

issn = "1098-3600",

publisher = "Elsevier BV",

number = "3",

}

Genomics England Research Consortium, Parry, DA, Martin, CA, Greene, P, Marsh, JA, Ambrose, JC, Arumugam, P, Baple, EL, Bleda, M, Boardman-Pretty, F, Boissiere, JM, Boustred, CR, Brittain, H, Caulfield, MJ, Chan, GC, Craig, CEH, Daugherty, LC, de Burca, A, Devereau, A, Elgar, G, Foulger, RE, Fowler, T, Furió-Tarí, P, Giess, A, Hackett, JM, Halai, D, Hamblin, A, Henderson, S, Holman, JE, Hubbard, TJB, Ibáñez, K, Jackson, R, Jones, LJ, Kasperaviciute, D, Kayikci, M, Kousathanas, A, Lahnstein, L, Lawson, K, Leigh, SEA, Leong, IUS, Lopez, FJ, Maleady-Crowe, F, Mason, J, McDonagh, EM, Moutsianas, L, Mueller, M, Murugaesu, N, Need, AC, Odhams, CA, Orioli, A, Patch, C, Perez-Gil, D, Pereira, MB, Polychronopoulos, D, Pullinger, J, Rahim, T, Rendon, A, Riesgo-Ferreiro, P, Rogers, T, Ryten, M, Savage, K, Sawant, K, Scott, RH, Siddiq, A, Sieghart, A, Smedley, D, Smith, KR, Smith, SC, Sosinsky, A, Spooner, W, Stevens, HE, Stuckey, A, Sultana, R, Tanguy, M, Thomas, ERA, Thompson, SR, Tregidgo, C, Tucci, A, Walsh, E, Watters, SA, Welland, MJ, Williams, E, Witkowska, K, Wood, SM, Zarowiecki, M, Blyth, M, Cox, H, Donnelly, D, Greenhalgh, L, Greville-Heygate, S, Harrison, V, Lachlan, K, McKenna, C, Quigley, AJ, Rea, G, Robertson, L, Suri, M & Jackson, AP 2021, '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, vol. 23, no. 3, pp. 408-414. https://doi.org/10.1038/s41436-020-00980-3

Heterozygous lamin B1 and lamin B2 variants cause primary microcephaly and define a novel laminopathy. / Genomics England Research Consortium; Parry, David A.; Martin, Carol Anne et al.
In: Genetics in medicine : official journal of the American College of Medical Genetics, Vol. 23, No. 3, 29.06.2021, p. 408-414.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Heterozygous lamin B1 and lamin B2 variants cause primary microcephaly and define a novel laminopathy

AU - Genomics England Research Consortium

AU - Parry, David A.

AU - Martin, Carol Anne

AU - Greene, Philip

AU - Marsh, Joseph A.

AU - Ambrose, J. C.

AU - Arumugam, P.

AU - Baple, E. L.

AU - Bleda, M.

AU - Boardman-Pretty, F.

AU - Boissiere, J. M.

AU - Boustred, C. R.

AU - Brittain, H.

AU - Caulfield, M. J.

AU - Chan, G. C.

AU - Craig, C. E. H.

AU - Daugherty, L. C.

AU - de Burca, A.

AU - Devereau, Andrew

AU - Elgar, G.

AU - Foulger, R. E.

AU - Fowler, T.

AU - Furió-Tarí, P.

AU - Giess, A.

AU - Hackett, J. M.

AU - Halai, D.

AU - Hamblin, A.

AU - Henderson, S.

AU - Holman, J. E.

AU - Hubbard, T. J. B.

AU - Ibáñez, K.

AU - Jackson, R.

AU - Jones, L. J.

AU - Kasperaviciute, D

AU - Kayikci, M.

AU - Kousathanas, A.

AU - Lahnstein, L.

AU - Lawson, K.

AU - Leigh, S. E. A.

AU - Leong, I. U. S.

AU - Lopez, F. J.

AU - Maleady-Crowe, F.

AU - Mason, J.

AU - McDonagh, E. M.

AU - Moutsianas, L.

AU - Mueller, M.

AU - Murugaesu, N.

AU - Need, A. C.

AU - Odhams, C. A.

AU - Orioli, A.

AU - Patch, C.

AU - Perez-Gil, D.

AU - Pereira, M. B.

AU - Polychronopoulos, D.

AU - Pullinger, J.

AU - Rahim, T.

AU - Rendon, A.

AU - Riesgo-Ferreiro, P.

AU - Rogers, T.

AU - Ryten, M.

AU - Savage, K.

AU - Sawant, K.

AU - Scott, R. H.

AU - Siddiq, A.

AU - Sieghart, A.

AU - Smedley, D.

AU - Smith, K. R.

AU - Smith, S. C.

AU - Sosinsky, A.

AU - Spooner, W.

AU - Stevens, H. E.

AU - Stuckey, A.

AU - Sultana, R.

AU - Tanguy, M.

AU - Thomas, E. R. A.

AU - Thompson, S. R.

AU - Tregidgo, C.

AU - Tucci, A.

AU - Walsh, E.

AU - Watters, S. A.

AU - Welland, M. J.

AU - Williams, E.

AU - Witkowska, K.

AU - Wood, S. M.

AU - Zarowiecki, M.

AU - Blyth, Moira

AU - Cox, Helen

AU - Donnelly, Deirdre

AU - Greenhalgh, Lynn

AU - Greville-Heygate, Stephanie

AU - Harrison, Victoria

AU - Lachlan, Katherine

AU - McKenna, Caoimhe

AU - Quigley, Alan J.

AU - Rea, Gillian

AU - Robertson, Lisa

AU - Suri, Mohnish

AU - Jackson, Andrew P.

PY - 2021/6/29

Y1 - 2021/6/29

N2 - 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.

AB - 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.

KW - LMNB1

KW - LMNB2

KW - laminopathy

KW - primary microcephaly

KW - neurodevelopmental disorder

UR - https://europepmc.org/articles/PMC7862057

U2 - 10.1038/s41436-020-00980-3

DO - 10.1038/s41436-020-00980-3

M3 - Article

C2 - 33033404

SN - 1098-3600

VL - 23

SP - 408

EP - 414

JO - Genetics in medicine : official journal of the American College of Medical Genetics

JF - Genetics in medicine : official journal of the American College of Medical Genetics

IS - 3

ER -

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

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Keywords

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