title: Large-scale discovery of novel genetic causes of developmental disorders.
abstract: Despite three decades of successful, predominantly phenotype-driven discovery of the genetic causes of monogenic disorders, up to half of children with severe developmental disorders of probable genetic origin remain without a genetic diagnosis. Particularly challenging are those disorders rare enough to have eluded recognition as a discrete clinical entity, those with highly variable clinical manifestations, and those that are difficult to distinguish from other, very similar, disorders. Here we demonstrate the power of using an unbiased genotype-driven approach to identify subsets of patients with similar disorders. By studying 1,133 children with severe, undiagnosed developmental disorders, and their parents, using a combination of exome sequencing and array-based detection of chromosomal rearrangements, we discovered 12 novel genes associated with developmental disorders. These newly implicated genes increase by 10% (from 28% to 31%) the proportion of children that could be diagnosed. Clustering of missense mutations in six of these newly implicated genes suggests that normal development is being perturbed by an activating or dominant-negative mechanism. Our findings demonstrate the value of adopting a comprehensive strategy, both genome-wide and nationwide, to elucidate the underlying causes of rare genetic disorders.
mesh_terms: D000293:Adolescent; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics; D002869:Chromosome Aberrations; D053487:DEAD-box RNA Helicases / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D002658:Developmental Disabilities / Q000175:diagnosis* / Q000235:genetics*; D034284:Dynamin I / Q000235:genetics; D059472:Exome / Q000235:genetics; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005799:Genes, Dominant / Q000235:genetics; D015894:Genome, Human / Q000235:genetics; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D020125:Mutation, Missense / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D010290:Parents; D010750:Phosphoproteins / Q000235:genetics; D063150:Polycomb Repressive Complex 1 / Q000235:genetics; D054648:Protein Phosphatase 2 / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D035583:Rare Diseases / Q000235:genetics; D012097:Repressor Proteins; D014157:Transcription Factors / Q000235:genetics; D019895:Transposases / Q000235:genetics; D006113:United Kingdom; D015027:Zebrafish / Q000235:genetics; D018797:Cell Cycle Proteins
chemical_list: D002352:Carrier Proteins; D002868:Chromosomal Proteins, Non-Histone; D053487:DEAD-box RNA Helicases; D004268:DNA-Binding Proteins; D034284:Dynamin I; D020662:Guanine Nucleotide Exchange Factors; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D063150:Polycomb Repressive Complex 1; D054648:Protein Phosphatase 2; D017346:Protein Serine-Threonine Kinases; D012097:Repressor Proteins; D014157:Transcription Factors; D019895:Transposases; C492178:ADNP protein, human; C486563:BCL11A protein, human; C555812:CHAMP1 protein, human; C489348:PCGF2 protein, human; C541037:POGZ protein, human; D018797:Cell Cycle Proteins; C517191:PPP2R1A protein, human; C525691:PPP2R5D protein, human; C501130:PURA protein, human; C119090:CERT1 protein, human; C099628:TRIO protein, human; C119332:DDX3X protein, human