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Quantifying the contribution of recessive coding variation to developmental disorders

Lookup NU author(s): Dr Miranda Splitt, Dr Michael Wright


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© 2018, American Association for the Advancement of Science. All rights reserved. We estimated the genome-wide contribution of recessive coding variation from 6,040 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 to 50% explained by de novo coding mutations. It was higher (31%) in patients with Pakistani ancestry, due 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 non-consanguineous individuals, and that the role of noncoding variants, incomplete penetrance, and polygenic mechanisms need further exploration.

Publication metadata

Author(s): 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

Publication type: Article

Publication status: Published

Journal: Science

Year: 2018

Volume: 362

Issue: 6419

Pages: 1161-1164

Print publication date: 07/12/2018

Online publication date: 08/11/2018

Acceptance date: 29/10/2018

ISSN (print): 0036-8075

ISSN (electronic): 1095-9203

Publisher: American Association for the Advancement of Science


DOI: 10.1126/science.aar6731


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