While the role of de novo and recessively-inherited coding variation in risk for rare developmental disorders (DDs) has been well established, the contribution of damaging variation dominantly-inherited from parents is less explored. Here, we investigated the contribution of rare coding variants to DDs by analyzing 13,452 individuals with DDs, 18,613 of their family members, and 3,943 controls using a combination of family-based and case/control analyses. In line with previous studies of other neuropsychiatric traits, we found a significant burden of rare (allele frequency < 1x10-5) predicted loss-of-function (pLoF) and damaging missense variants, the vast majority of which are inherited from apparently unaffected parents. These predominantly inherited burdens are strongest in DD-associated genes or those intolerant of pLoF variation in the general population, however we estimate that ~10% of the excess of these variants in DD cases is found within the DD-associated genes, implying many more risk loci are yet to be identified. We found similar, but attenuated, burdens when comparing the unaffected parents of individuals with DDs to controls, indicating that parents have elevated risk of DDs due to these rare variants, which are overtransmitted to their affected children. We estimate that 6-8.5% of the population attributable risk for DDs are due to rare pLoF variants in those genes intolerant of pLoF variation in the general population. Finally, we apply a Bayesian framework to combine evidence from these analyses of rare, mostly-inherited variants with prior de novo mutation burden analyses to highlight an additional 25 candidate DD-associated genes for further follow up.

K.E.S. has received support from Microsoft for work related to rare disease diagnostics. E.J.G. is an employee of and holds shares in Insmed Incorporated. M.E.H. is a co-founder of, consultant to and holds shares in Congenica, a genetics diagnostic company. The remaining authors declare no competing interests.

This study makes use of DECIPHER, which is funded by the Wellcome Trust. This research was funded in part by Wellcome (grant no. 220540/Z/20/A, Wellcome Sanger Institute Quinquennial Review 2021 - 2026).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study was approved by the UK Research Ethics Committee (10/H0305/83 granted by the Cambridge South Research Ethics Committee, and GEN/284/12 granted by the Republic of Ireland Research Ethics Committee)

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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Sequence and variant-level data and phenotype data from the DDD study data are available on the European Genome-phenome Archive (EGA; https://www.ebi.ac.uk/ega/) with study ID EGAS00001000775. Exome sequencing for the INTERVAL cohort is also available on EGA with study ID EGAD00001002221. Previously described databases were from the Genome Aggregation Database (gnomAD v2.1.1; https://gnomad.broadinstitute.org/downloads) and the Developmental Disorders Genotype-Phenotype Database (DDG2P; https://www.ebi.ac.uk/gene2phenotype/downloads).