Prevalence and architecture of de novo mutations in developmental disorders
| Autor: | Deciphering Developmental Disorders Study |
|---|---|
| Přispěvatelé: | Apollo - University of Cambridge Repository |
| Rok vydání: | 2020 |
| Předmět: |
Adult
Male Parents Heredity Adolescent Chromosomal Proteins Non-Histone Developmental Disabilities Close relatives Nerve Tissue Proteins Genome Autoantigens Cohort Studies DEAD-box RNA Helicases Young Adult CDC2 Protein Kinase Prevalence Medicine Humans Exome Casein Kinase II Child Gene De novo mutations Exome sequencing Genetics Homeodomain Proteins Sex Characteristics business.industry Obstetrics and Gynecology Parental Ages General Medicine Histone-Lysine N-Methyltransferase Sequence Analysis DNA Middle Aged Phenotype DNA-Binding Proteins Protein Phosphatase 2C Repressor Proteins ras GTPase-Activating Proteins Cohort Mutation Female business Myeloid-Lymphoid Leukemia Protein Mi-2 Nucleosome Remodeling and Deacetylase Complex Transcription Factors |
| ISSN: | 0028-0836 1476-4687 |
| DOI: | 10.17863/cam.48939 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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