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

Research output: Contribution to journalArticlepeer-review

119 Citations (Scopus)


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 languageEnglish
Pages (from-to)1161-1164
Number of pages4
Issue number6419
Publication statusPublished - Dec 7 2018
Externally publishedYes

ASJC Scopus subject areas

  • General


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