title: Prevalence and architecture of de novo mutations in developmental disorders.
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.
mesh_terms: D000293:Adolescent; D000328:Adult; D001324:Autoantigens / Q000235:genetics; D016203:CDC2 Protein Kinase / Q000235:genetics; D047390:Casein Kinase II / Q000235:genetics; D002648:Child; D002868:Chromosomal Proteins, Non-Histone; D015331:Cohort Studies; D053487:DEAD-box RNA Helicases / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D002658:Developmental Disabilities / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005260:Female; D040941:Heredity / Q000235:genetics; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex / Q000235:genetics; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D010290:Parents; D010641:Phenotype; D015995:Prevalence; D000071636:Protein Phosphatase 2C / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D017422:Sequence Analysis, DNA; D012727:Sex Characteristics; D014157:Transcription Factors / Q000235:genetics; D055815:Young Adult; D020703:ras GTPase-Activating Proteins / Q000235:genetics
chemical_list: C492178:ADNP protein, human; C492515:ANKRD11 protein, human; C497837:ARID1B protein, human; D001324:Autoantigens; C115323:CHD4 protein, human; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C497422:KMT2A protein, human; C120701:MSL3 protein, human; D009419:Nerve Tissue Proteins; D012097:Repressor Proteins; C484739:SYNGAP1 protein, human; C114750:TCF20 protein, human; D014157:Transcription Factors; C115048:ZBTB18 protein, human; D020703:ras GTPase-Activating Proteins; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C570325:CSNK2A1 protein, human; D047390:Casein Kinase II; D016203:CDC2 Protein Kinase; C072262:CDK13 protein, human; C000607458:PPM1D protein, human; D000071636:Protein Phosphatase 2C; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex; C119332:DDX3X protein, human; D053487:DEAD-box RNA Helicases