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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.
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
URL: https://doi.org/10.1126/science.aar6731
DOI: 10.1126/science.aar6731
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