| Literature DB >> 30409806 |
Hilary C Martin1, Wendy D Jones2,3, Rebecca McIntyre2, Gabriela Sanchez-Andrade2, Mark Sanderson2, James D Stephenson2,4, Carla P Jones2, Juliet Handsaker2, Giuseppe Gallone2, Michaela Bruntraeger2, Jeremy F McRae2, Elena Prigmore2, Patrick Short2, Mari Niemi2, Joanna Kaplanis2, Elizabeth J Radford2,5, Nadia Akawi6, Meena Balasubramanian7, John Dean8, Rachel Horton9, Alice Hulbert10, Diana S Johnson7, Katie Johnson11, Dhavendra Kumar12, Sally Ann Lynch13, Sarju G Mehta14, Jenny Morton15, Michael J Parker16, Miranda Splitt17, Peter D Turnpenny18, Pradeep C Vasudevan19, Michael Wright17, Andrew Bassett2, Sebastian S Gerety2, Caroline F Wright20, David R FitzPatrick21, Helen V Firth2,14, Matthew E Hurles2, Jeffrey C Barrett1.
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.Entities:
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Year: 2018 PMID： 30409806 PMCID： PMC6726470 DOI： 10.1126/science.aar6731
Source DB: PubMed Journal: Science ISSN： 0036-8075 Impact factor: 47.728