Quantifying the contribution of recessive coding variation to developmental disorders

Hilary C. Martin; Wendy D. Jones; Rebecca McIntyre; Gabriela Sanchez-Andrade; Mark Sanderson; James D. Stephenson; Carla P. Jones; Juliet Handsaker; Giuseppe Gallone; Michaela Bruntraeger; Jeremy F. McRae; Elena Prigmore; Patrick Short; Mari Niemi; Joanna Kaplanis; Elizabeth J. Radford; Nadia Akawi; Meena Balasubramanian; John Dean; Rachel Horton; Alice Hulbert; Diana S. Johnson; Katie Johnson; Dhavendra Kumar; Sally Ann Lynch; Sarju G. Mehta; Jenny Morton; Michael J. Parker; Miranda Splitt; Peter D. Turnpenny; Pradeep C. Vasudevan; Michael Wright; Andrew Bassett; Sebastian S. Gerety; Caroline F. Wright; David R. FitzPatrick; Helen V. Firth; Matthew E. Hurles; Jeffrey C. Barrett

doi:10.1126/science.aar6731

Quantifying the contribution of recessive coding variation to developmental disorders

Hilary C. Martin, Wendy D. Jones, Rebecca McIntyre, Gabriela Sanchez-Andrade, Mark Sanderson, James D. Stephenson, Carla P. Jones, Juliet Handsaker, Giuseppe Gallone, Michaela Bruntraeger, Jeremy F. McRae, Elena Prigmore, Patrick Short, Mari Niemi, Joanna Kaplanis, Elizabeth J. Radford, Nadia Akawi, Meena Balasubramanian, John Dean, Rachel HortonAlice Hulbert, Diana S. Johnson, Katie Johnson, Dhavendra Kumar, Sally Ann Lynch, Sarju G. Mehta, Jenny Morton, Michael J. Parker, Miranda Splitt, Peter D. Turnpenny, Pradeep C. Vasudevan, Michael Wright, Andrew Bassett, Sebastian S. Gerety, Caroline F. Wright, David R. FitzPatrick, Helen V. Firth, Matthew E. Hurles, Jeffrey C. Barrett

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Abstract

We estimated the genome-wide contribution of recessive coding variation in 6040 families from the Deciphering Developmental Disorders study. The proportion of cases attributable to recessive coding variants was 3.6% in patients of European ancestry, compared with 50% explained by de novo coding mutations. It was higher (31%) in patients with Pakistani ancestry, owing to elevated autozygosity. Half of this recessive burden is attributable to known genes. We identified two genes not previously associated with recessive developmental disorders, KDM5B and EIF3F, and functionally validated them with mouse and cellular models. Our results suggest that recessive coding variants account for a small fraction of currently undiagnosed nonconsanguineous individuals, and that the role of noncoding variants, incomplete penetrance, and polygenic mechanisms need further exploration.

Original language	English
Pages (from-to)	1161-1164
Number of pages	4
Journal	Science
Volume	362
Issue number	6419
DOIs	https://doi.org/10.1126/science.aar6731
Publication status	Published - Dec 7 2018
Externally published	Yes

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Martin, H. C., Jones, W. D., McIntyre, R., Sanchez-Andrade, G., Sanderson, M., Stephenson, J. D., Jones, C. P., Handsaker, J., Gallone, G., Bruntraeger, M., McRae, J. F., Prigmore, E., Short, P., Niemi, M., Kaplanis, J., Radford, E. J., Akawi, N., Balasubramanian, M., Dean, J., ... Barrett, J. C. (2018). Quantifying the contribution of recessive coding variation to developmental disorders. Science, 362(6419), 1161-1164. https://doi.org/10.1126/science.aar6731

Martin, HC, Jones, WD, McIntyre, R, Sanchez-Andrade, G, Sanderson, M, Stephenson, JD, Jones, CP, Handsaker, J, Gallone, G, Bruntraeger, M, McRae, JF, Prigmore, E, Short, P, Niemi, M, Kaplanis, J, Radford, EJ, Akawi, N, Balasubramanian, M, Dean, J, Horton, R, Hulbert, A, Johnson, DS, Johnson, K, Kumar, D, Lynch, SA, Mehta, SG, Morton, J, Parker, MJ, Splitt, M, Turnpenny, PD, Vasudevan, PC, Wright, M, Bassett, A, Gerety, SS, Wright, CF, FitzPatrick, DR, Firth, HV, Hurles, ME & Barrett, JC 2018, 'Quantifying the contribution of recessive coding variation to developmental disorders', Science, vol. 362, no. 6419, pp. 1161-1164. https://doi.org/10.1126/science.aar6731

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title = "Quantifying the contribution of recessive coding variation to developmental disorders",

abstract = "We estimated the genome-wide contribution of recessive coding variation in 6040 families from the Deciphering Developmental Disorders study. The proportion of cases attributable to recessive coding variants was 3.6% in patients of European ancestry, compared with 50% explained by de novo coding mutations. It was higher (31%) in patients with Pakistani ancestry, owing to elevated autozygosity. Half of this recessive burden is attributable to known genes. We identified two genes not previously associated with recessive developmental disorders, KDM5B and EIF3F, and functionally validated them with mouse and cellular models. Our results suggest that recessive coding variants account for a small fraction of currently undiagnosed nonconsanguineous individuals, and that the role of noncoding variants, incomplete penetrance, and polygenic mechanisms need further exploration.",

author = "Martin, {Hilary C.} and Jones, {Wendy D.} and Rebecca McIntyre and Gabriela Sanchez-Andrade and Mark Sanderson and Stephenson, {James D.} and Jones, {Carla P.} and Juliet Handsaker and Giuseppe Gallone and Michaela Bruntraeger and McRae, {Jeremy F.} and Elena Prigmore and Patrick Short and Mari Niemi and Joanna Kaplanis and Radford, {Elizabeth J.} and Nadia Akawi and Meena Balasubramanian and John Dean and Rachel Horton and Alice Hulbert and Johnson, {Diana S.} and Katie Johnson and Dhavendra Kumar and Lynch, {Sally Ann} and Mehta, {Sarju G.} and Jenny Morton and Parker, {Michael J.} and Miranda Splitt and Turnpenny, {Peter D.} and Vasudevan, {Pradeep C.} and Michael Wright and Andrew Bassett and Gerety, {Sebastian S.} and Wright, {Caroline F.} and FitzPatrick, {David R.} and Firth, {Helen V.} and Hurles, {Matthew E.} and Barrett, {Jeffrey C.}",

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year = "2018",

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doi = "10.1126/science.aar6731",

language = "English",

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AU - Martin, Hilary C.

AU - Jones, Wendy D.

AU - McIntyre, Rebecca

AU - Sanchez-Andrade, Gabriela

AU - Sanderson, Mark

AU - Stephenson, James D.

AU - Jones, Carla P.

AU - Handsaker, Juliet

AU - Gallone, Giuseppe

AU - Bruntraeger, Michaela

AU - McRae, Jeremy F.

AU - Prigmore, Elena

AU - Short, Patrick

AU - Niemi, Mari

AU - Kaplanis, Joanna

AU - Radford, Elizabeth J.

AU - Akawi, Nadia

AU - Balasubramanian, Meena

AU - Dean, John

AU - Horton, Rachel

AU - Hulbert, Alice

AU - Johnson, Diana S.

AU - Johnson, Katie

AU - Kumar, Dhavendra

AU - Lynch, Sally Ann

AU - Mehta, Sarju G.

AU - Morton, Jenny

AU - Parker, Michael J.

AU - Splitt, Miranda

AU - Turnpenny, Peter D.

AU - Vasudevan, Pradeep C.

AU - Wright, Michael

AU - Bassett, Andrew

AU - Gerety, Sebastian S.

AU - Wright, Caroline F.

AU - FitzPatrick, David R.

AU - Firth, Helen V.

AU - Hurles, Matthew E.

AU - Barrett, Jeffrey C.

PY - 2018/12/7

Y1 - 2018/12/7

N2 - We estimated the genome-wide contribution of recessive coding variation in 6040 families from the Deciphering Developmental Disorders study. The proportion of cases attributable to recessive coding variants was 3.6% in patients of European ancestry, compared with 50% explained by de novo coding mutations. It was higher (31%) in patients with Pakistani ancestry, owing to elevated autozygosity. Half of this recessive burden is attributable to known genes. We identified two genes not previously associated with recessive developmental disorders, KDM5B and EIF3F, and functionally validated them with mouse and cellular models. Our results suggest that recessive coding variants account for a small fraction of currently undiagnosed nonconsanguineous individuals, and that the role of noncoding variants, incomplete penetrance, and polygenic mechanisms need further exploration.

AB - We estimated the genome-wide contribution of recessive coding variation in 6040 families from the Deciphering Developmental Disorders study. The proportion of cases attributable to recessive coding variants was 3.6% in patients of European ancestry, compared with 50% explained by de novo coding mutations. It was higher (31%) in patients with Pakistani ancestry, owing to elevated autozygosity. Half of this recessive burden is attributable to known genes. We identified two genes not previously associated with recessive developmental disorders, KDM5B and EIF3F, and functionally validated them with mouse and cellular models. Our results suggest that recessive coding variants account for a small fraction of currently undiagnosed nonconsanguineous individuals, and that the role of noncoding variants, incomplete penetrance, and polygenic mechanisms need further exploration.

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Quantifying the contribution of recessive coding variation to developmental disorders

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