10.17863/CAM.48939
Deciphering Developmental Disorders Study
Prevalence and architecture of de novo mutations in developmental disorders.
Springer Science and Business Media LLC
2017
Adolescent
Adult
Autoantigens
CDC2 Protein Kinase
Casein Kinase II
Child
Chromosomal Proteins, Non-Histone
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
Apollo - University of Cambridge Repository
University of Cambridge
013meh722
2020-02-08
2020-02-08
2017-02-23
eng
Article
https://www.repository.cam.ac.uk/handle/1810/301871
10.1038/nature21062
All rights reserved
open.access
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.
Medical Research Council
G0800270