RT Journal Article
SR Electronic
T1 Autosomal recessive coding variants explain only a small proportion of undiagnosed developmental disorders in the British Isles
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 201533
DO 10.1101/201533
A1 Hilary C. Martin
A1 Wendy D. Jones
A1 James Stephenson
A1 Juliet Handsaker
A1 Giuseppe Gallone
A1 Jeremy F. McRae
A1 Elena Prigmore
A1 Patrick Short
A1 Mari Niemi
A1 Joanna Kaplanis
A1 Elizabeth Radford
A1 Nadia Akawi
A1 Meena Balasubramanian
A1 John Dean
A1 Rachel Horton
A1 Alice Hulbert
A1 Diana S. Johnson
A1 Katie Johnson
A1 Dhavendra Kumar
A1 Sally Ann Lynch
A1 Sarju G. Mehta
A1 Jenny Morton
A1 Michael J. Parker
A1 Miranda Splitt
A1 Peter D Turnpenny
A1 Pradeep C. Vasudevan
A1 Michael Wright
A1 Caroline F. Wright
A1 David R. FitzPatrick
A1 Helen V. Firth
A1 Matthew E. Hurles
A1 Jeffrey C. Barrett
A1 on behalf of the DDD Study
YR 2017
UL http://biorxiv.org/content/early/2017/10/13/201533.abstract
AB We analyzed 7,448 exome-sequenced families from the Deciphering Developmental Disorders study to search for recessive coding diagnoses. We estimated that the proportion of cases attributable to recessive coding variants is 3.6% for patients of European ancestry, and 30.9% for those of Pakistani ancestry due to elevated autozygosity. We tested every gene for an excess of damaging homozygous or compound heterozygous genotypes, and found that known recessive genes showed a significant tendency towards having lower p-values (Kolmogorov-Smirnov p=3.3×10−16). Three genes passed stringent Bonferroni correction, including a new disease gene, EIF3F, and KDM5B, which has previously been reported as a dominant disease gene. KDM5B appears to follow a complex mode of inheritance, in which heterozygous loss-of-function variants (LoFs) show incomplete penetrance and biallelic LoFs are fully penetrant. Our results suggest that a large proportion of undiagnosed developmental disorders remain to be explained by other factors, such as noncoding variants and polygenic risk.