The contribution of X-linked coding variation to severe developmental disorders

Hilary C. Martin; Eugene J. Gardner; Kaitlin E. Samocha; Joanna Kaplanis; Nadia Akawi; Alejandro Sifrim; Ruth Y. Eberhardt; Ana Lisa Taylor Tavares; Matthew D.C. Neville; Mari E.K. Niemi; Giuseppe Gallone; Jeremy McRae; Silvia Borras; Caroline Clark; John Dean; Zosia Miedzybrodzka; Alison Ross; Stephen Tennant; Tabib Dabir; Deirdre Donnelly; Mervyn Humphreys; Alex Magee; Vivienne McConnell; Shane McKee; Susan McNerlan; Patrick J. Morrison; Gillian Rea; Fiona Stewart; Trevor Cole; Nicola Cooper; Lisa Cooper-Charles; Helen Cox; Lily Islam; Joanna Jarvis; Rebecca Keelagher; Derek Lim; Dominic McMullan; Jenny Morton; Swati Naik; Mary O’Driscoll; Kai Ren Ong; Deborah Osio; Nicola Ragge; Julie Vogt; Denise Williams; Simon Bodek; Alan Donaldson; Alison Hills; K Low; R Newbury-Ecob; AM Norman; E Roberts; I Scurr; S Smithson; M Tooley; S Abbs; R Armstrong; C Dunn; S Holden; S-M Park; J Paterson; L Raymond; E Reid; R Sandford; I Simonic; M Tischkowitz; G Woods; L Bradley; J Comerford; A Green; S Lynch; S McQuaid; B Mullaney; J Berg; D Goudie; E Mavrak; J McLean; C McWilliam; E Reavey; T Azam; S Turton; E Cleary; A Jackson; W Lam; A Lampe; D Moore; M Porteous; E Baple; Júlia Baptista; C Brewer; B Castle; E Kivuva; M Owens; J Rankin; C Shaw-Smith

doi:10.1038/s41467-020-20852-3

The contribution of X-linked coding variation to severe developmental disorders

Hilary C. Martin^*, Eugene J. Gardner, Kaitlin E. Samocha, Joanna Kaplanis, Nadia Akawi, Alejandro Sifrim, Ruth Y. Eberhardt, Ana Lisa Taylor Tavares, Matthew D.C. Neville, Mari E.K. Niemi, Giuseppe Gallone, Jeremy McRae, Silvia Borras, Caroline Clark, John Dean, Zosia Miedzybrodzka, Alison Ross, Stephen Tennant, Tabib Dabir, Deirdre DonnellyMervyn Humphreys, Alex Magee, Vivienne McConnell, Shane McKee, Susan McNerlan, Patrick J. Morrison, Gillian Rea, Fiona Stewart, Trevor Cole, Nicola Cooper, Lisa Cooper-Charles, Helen Cox, Lily Islam, Joanna Jarvis, Rebecca Keelagher, Derek Lim, Dominic McMullan, Jenny Morton, Swati Naik, Mary O’Driscoll, Kai Ren Ong, Deborah Osio, Nicola Ragge, Julie Vogt, Denise Williams, Simon Bodek, Alan Donaldson, Alison Hills, K Low, R Newbury-Ecob, AM Norman, E Roberts, I Scurr, S Smithson, M Tooley, S Abbs, R Armstrong, C Dunn, S Holden, S-M Park, J Paterson, L Raymond, E Reid, R Sandford, I Simonic, M Tischkowitz, G Woods, L Bradley, J Comerford, A Green, S Lynch, S McQuaid, B Mullaney, J Berg, D Goudie, E Mavrak, J McLean, C McWilliam, E Reavey, T Azam, S Turton, E Cleary, A Jackson, W Lam, A Lampe, D Moore, M Porteous, E Baple, Júlia Baptista, C Brewer, B Castle, E Kivuva, M Owens, J Rankin, C Shaw-Smith

^*Corresponding author for this work

Peninsula Medical School

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

Abstract

AbstractOver 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders.

Original language	English
Number of pages	0
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-20852-3
Publication status	E-pub ahead of print - 27 Jan 2021

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10.1038/s41467-020-20852-3

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Martin, H. C., Gardner, E. J., Samocha, K. E., Kaplanis, J., Akawi, N., Sifrim, A., Eberhardt, R. Y., Tavares, A. L. T., Neville, M. D. C., Niemi, M. E. K., Gallone, G., McRae, J., Borras, S., Clark, C., Dean, J., Miedzybrodzka, Z., Ross, A., Tennant, S., Dabir, T., ... Shaw-Smith, C. (2021). The contribution of X-linked coding variation to severe developmental disorders. Nature Communications, 12(1). Advance online publication. https://doi.org/10.1038/s41467-020-20852-3

@article{1d8f5190b1b7452987a53a9dfe2e4dd6,

title = "The contribution of X-linked coding variation to severe developmental disorders",

abstract = "AbstractOver 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders.",

author = "Martin, {Hilary C.} and Gardner, {Eugene J.} and Samocha, {Kaitlin E.} and Joanna Kaplanis and Nadia Akawi and Alejandro Sifrim and Eberhardt, {Ruth Y.} and Tavares, {Ana Lisa Taylor} and Neville, {Matthew D.C.} and Niemi, {Mari E.K.} and Giuseppe Gallone and Jeremy McRae and Silvia Borras and Caroline Clark and John Dean and Zosia Miedzybrodzka and Alison Ross and Stephen Tennant and Tabib Dabir and Deirdre Donnelly and Mervyn Humphreys and Alex Magee and Vivienne McConnell and Shane McKee and Susan McNerlan and Morrison, {Patrick J.} and Gillian Rea and Fiona Stewart and Trevor Cole and Nicola Cooper and Lisa Cooper-Charles and Helen Cox and Lily Islam and Joanna Jarvis and Rebecca Keelagher and Derek Lim and Dominic McMullan and Jenny Morton and Swati Naik and Mary O{\textquoteright}Driscoll and Ong, {Kai Ren} and Deborah Osio and Nicola Ragge and Julie Vogt and Denise Williams and Simon Bodek and Alan Donaldson and Alison Hills and K Low and R Newbury-Ecob and AM Norman and E Roberts and I Scurr and S Smithson and M Tooley and S Abbs and R Armstrong and C Dunn and S Holden and S-M Park and J Paterson and L Raymond and E Reid and R Sandford and I Simonic and M Tischkowitz and G Woods and L Bradley and J Comerford and A Green and S Lynch and S McQuaid and B Mullaney and J Berg and D Goudie and E Mavrak and J McLean and C McWilliam and E Reavey and T Azam and S Turton and E Cleary and A Jackson and W Lam and A Lampe and D Moore and M Porteous and E Baple and J{\'u}lia Baptista and C Brewer and B Castle and E Kivuva and M Owens and J Rankin and C Shaw-Smith",

year = "2021",

month = jan,

day = "27",

doi = "10.1038/s41467-020-20852-3",

language = "English",

volume = "12",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Martin, HC, Gardner, EJ, Samocha, KE, Kaplanis, J, Akawi, N, Sifrim, A, Eberhardt, RY, Tavares, ALT, Neville, MDC, Niemi, MEK, Gallone, G, McRae, J, Borras, S, Clark, C, Dean, J, Miedzybrodzka, Z, Ross, A, Tennant, S, Dabir, T, Donnelly, D, Humphreys, M, Magee, A, McConnell, V, McKee, S, McNerlan, S, Morrison, PJ, Rea, G, Stewart, F, Cole, T, Cooper, N, Cooper-Charles, L, Cox, H, Islam, L, Jarvis, J, Keelagher, R, Lim, D, McMullan, D, Morton, J, Naik, S, O’Driscoll, M, Ong, KR, Osio, D, Ragge, N, Vogt, J, Williams, D, Bodek, S, Donaldson, A, Hills, A, Low, K, Newbury-Ecob, R, Norman, AM, Roberts, E, Scurr, I, Smithson, S, Tooley, M, Abbs, S, Armstrong, R, Dunn, C, Holden, S, Park, S-M, Paterson, J, Raymond, L, Reid, E, Sandford, R, Simonic, I, Tischkowitz, M, Woods, G, Bradley, L, Comerford, J, Green, A, Lynch, S, McQuaid, S, Mullaney, B, Berg, J, Goudie, D, Mavrak, E, McLean, J, McWilliam, C, Reavey, E, Azam, T, Turton, S, Cleary, E, Jackson, A, Lam, W, Lampe, A, Moore, D, Porteous, M, Baple, E, Baptista, J, Brewer, C, Castle, B, Kivuva, E, Owens, M, Rankin, J & Shaw-Smith, C 2021, 'The contribution of X-linked coding variation to severe developmental disorders', Nature Communications, vol. 12, no. 1. https://doi.org/10.1038/s41467-020-20852-3

TY - JOUR

T1 - The contribution of X-linked coding variation to severe developmental disorders

AU - Martin, Hilary C.

AU - Gardner, Eugene J.

AU - Samocha, Kaitlin E.

AU - Kaplanis, Joanna

AU - Akawi, Nadia

AU - Sifrim, Alejandro

AU - Eberhardt, Ruth Y.

AU - Tavares, Ana Lisa Taylor

AU - Neville, Matthew D.C.

AU - Niemi, Mari E.K.

AU - Gallone, Giuseppe

AU - McRae, Jeremy

AU - Borras, Silvia

AU - Clark, Caroline

AU - Dean, John

AU - Miedzybrodzka, Zosia

AU - Ross, Alison

AU - Tennant, Stephen

AU - Dabir, Tabib

AU - Donnelly, Deirdre

AU - Humphreys, Mervyn

AU - Magee, Alex

AU - McConnell, Vivienne

AU - McKee, Shane

AU - McNerlan, Susan

AU - Morrison, Patrick J.

AU - Rea, Gillian

AU - Stewart, Fiona

AU - Cole, Trevor

AU - Cooper, Nicola

AU - Cooper-Charles, Lisa

AU - Cox, Helen

AU - Islam, Lily

AU - Jarvis, Joanna

AU - Keelagher, Rebecca

AU - Lim, Derek

AU - McMullan, Dominic

AU - Morton, Jenny

AU - Naik, Swati

AU - O’Driscoll, Mary

AU - Ong, Kai Ren

AU - Osio, Deborah

AU - Ragge, Nicola

AU - Vogt, Julie

AU - Williams, Denise

AU - Bodek, Simon

AU - Donaldson, Alan

AU - Hills, Alison

AU - Low, K

AU - Newbury-Ecob, R

AU - Norman, AM

AU - Roberts, E

AU - Scurr, I

AU - Smithson, S

AU - Tooley, M

AU - Abbs, S

AU - Armstrong, R

AU - Dunn, C

AU - Holden, S

AU - Park, S-M

AU - Paterson, J

AU - Raymond, L

AU - Reid, E

AU - Sandford, R

AU - Simonic, I

AU - Tischkowitz, M

AU - Woods, G

AU - Bradley, L

AU - Comerford, J

AU - Green, A

AU - Lynch, S

AU - McQuaid, S

AU - Mullaney, B

AU - Berg, J

AU - Goudie, D

AU - Mavrak, E

AU - McLean, J

AU - McWilliam, C

AU - Reavey, E

AU - Azam, T

AU - Turton, S

AU - Cleary, E

AU - Jackson, A

AU - Lam, W

AU - Lampe, A

AU - Moore, D

AU - Porteous, M

AU - Baple, E

AU - Baptista, Júlia

AU - Brewer, C

AU - Castle, B

AU - Kivuva, E

AU - Owens, M

AU - Rankin, J

AU - Shaw-Smith, C

PY - 2021/1/27

Y1 - 2021/1/27

N2 - AbstractOver 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders.

AB - AbstractOver 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders.

U2 - 10.1038/s41467-020-20852-3

DO - 10.1038/s41467-020-20852-3

M3 - Article

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

ER -

The contribution of X-linked coding variation to severe developmental disorders

Abstract

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