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The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year.

Original publication

DOI

10.1038/nature21062

Type

Journal article

Journal

Nature

Volume

542

Pages

433 - 438

Keywords

Adolescent, Adult, Autoantigens, CDC2 Protein Kinase, Casein Kinase II, Child, Cohort Studies, DEAD-box RNA Helicases, DNA-Binding Proteins, Developmental Disabilities, Exome, Female, Heredity, Histone-Lysine N-Methyltransferase, Homeodomain Proteins, Humans, Male, Mi-2 Nucleosome Remodeling and Deacetylase Complex, Middle Aged, Mutation, Myeloid-Lymphoid Leukemia Protein, Nerve Tissue Proteins, Parents, Phenotype, Prevalence, Protein Phosphatase 2C, Repressor Proteins, Sequence Analysis, DNA, Sex Characteristics, Transcription Factors, Young Adult, ras GTPase-Activating Proteins