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Despite three decades of successful, predominantly phenotype-driven discovery of the genetic causes of monogenic disorders1, 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 approach2 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 sequencing3-11 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.
We established a network to recruit 1,133 children (median age 5.5 years, Extended DataFig.1a) with diverse, severeundiagnosed developmental disorders, through all 24 regional genetics services of the UK National Health Service and Republic of Ireland. Among the most commonly observed phenotypes (Extended Data Fig. 1b and Supplementary Table 1) were intellectual disability or developmental delay (87% of children), abnormalities revealed by cranial MRI (30%), seizures (24%), and congenital heart defects (11%). These children are predominantly (,90%) of northwest European ancestry (Extended Data Fig. 1c), with 47 pairs of parents (4.1%) exhibiting kinship equivalent to, or in excess of, second cousins (Extended Data Fig. 1d and Supplementary Information). In mostfamilies (849 of 1,101) the child was the onlyaffected family member, but 111 children had one or more parents with a similar developmental disorder, and 124 had a similarly affected sibling (Supplementary Information). Prior clinical genetic testing would have already diagnosed many children with easily recognized syndromes, or large pathogenic deletions and duplications, enriching this research cohort for less distinct syndromes and novel genetic disorders.
We sequenced the exomes of 1,133 children with developmental disorders and their parents, from 1,101 families,...