Prevalence and architecture of de novo mutations in developmental disorders View Full Text


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Article Info

DATE

2017-01-25

ABSTRACT

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. More... »

PAGES

433-438

References to SciGraph publications

  • 2014-12-24. Large-scale discovery of novel genetic causes of developmental disorders in NATURE
  • 2011-08-14. A copy number variation morbidity map of developmental delay in NATURE GENETICS
  • 2013-08-25. DeNovoGear: de novo indel and point mutation discovery and phasing in NATURE METHODS
  • 2013-05-12. De novo mutations in histone-modifying genes in congenital heart disease in NATURE
  • 2016-08-01. Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing in NATURE GENETICS
  • 2014-10-29. Synaptic, transcriptional and chromatin genes disrupted in autism in NATURE
  • 2014-10-29. The contribution of de novo coding mutations to autism spectrum disorder in NATURE
  • 2016-08-17. Analysis of protein-coding genetic variation in 60,706 humans in NATURE
  • 2012-08-22. Rate of de novo mutations and the importance of father’s age to disease risk in NATURE
  • 2013-09-03. Rare-disease genetics in the era of next-generation sequencing: discovery to translation in NATURE REVIEWS GENETICS
  • 2012-04-04. De novo mutations revealed by whole-exome sequencing are strongly associated with autism in NATURE
  • 2014-06-04. Genome sequencing identifies major causes of severe intellectual disability in NATURE
  • 2015-10-05. Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families in NATURE GENETICS
  • 2016-11-02. Dominant variants in the splicing factor PUF60 cause a recognizable syndrome with intellectual disability, heart defects and short stature in EUROPEAN JOURNAL OF HUMAN GENETICS
  • 2014-07-19. Variant detection sensitivity and biases in whole genome and exome sequencing in BMC BIOINFORMATICS
  • 2014-09-01. A framework for the interpretation of de novo mutation in human disease in NATURE GENETICS
  • 2016-01-19. New observations on maternal age effect on germline de novo mutations in NATURE COMMUNICATIONS
  • 2016-04-05. De novo mutations in CSNK2A1 are associated with neurodevelopmental abnormalities and dysmorphic features in HUMAN GENETICS
  • 2012-10-31. An integrated map of genetic variation from 1,092 human genomes in NATURE
  • 2016-08-01. Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability in NATURE NEUROSCIENCE
  • 2015-12-14. Timing, rates and spectra of human germline mutation in NATURE GENETICS
  • 2012-04-04. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations in NATURE
  • 2013-08-11. De novo mutations in epileptic encephalopathies in NATURE
  • 2014-01-22. De novo mutations in schizophrenia implicate synaptic networks in NATURE
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    62 schema:description 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.
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