TY - JOUR T1 - Autosomal recessive coding variants explain only a small proportion of undiagnosed developmental disorders in the British Isles JF - bioRxiv DO - 10.1101/201533 SP - 201533 AU - Hilary C. Martin AU - Wendy D. Jones AU - James Stephenson AU - Juliet Handsaker AU - Giuseppe Gallone AU - Jeremy F. McRae AU - Elena Prigmore AU - Patrick Short AU - Mari Niemi AU - Joanna Kaplanis AU - Elizabeth Radford AU - Nadia Akawi AU - Meena Balasubramanian AU - John Dean AU - Rachel Horton AU - Alice Hulbert AU - Diana S. Johnson AU - Katie Johnson AU - Dhavendra Kumar AU - Sally Ann Lynch AU - Sarju G. Mehta AU - Jenny Morton AU - Michael J. Parker AU - Miranda Splitt AU - Peter D Turnpenny AU - Pradeep C. Vasudevan AU - Michael Wright AU - Caroline F. Wright AU - David R. FitzPatrick AU - Helen V. Firth AU - Matthew E. Hurles AU - Jeffrey C. Barrett AU - on behalf of the DDD Study Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/10/13/201533.abstract N2 - 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. ER -