Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication

DOI

10.1038/nature14135

Type

Journal article

Journal

Nature

Publication Date

12/03/2015

Volume

519

Pages

223 - 228

Keywords

Adolescent, Animals, Carrier Proteins, Child, Child, Preschool, Chromosomal Proteins, Non-Histone, Chromosome Aberrations, DEAD-box RNA Helicases, DNA-Binding Proteins, Developmental Disabilities, Dynamin I, Exome, Female, Gene Expression Regulation, Developmental, Genes, Dominant, Genome, Human, Guanine Nucleotide Exchange Factors, Homeodomain Proteins, Humans, Infant, Infant, Newborn, Male, Mutation, Missense, Nerve Tissue Proteins, Nuclear Proteins, Parents, Phosphoproteins, Polycomb Repressive Complex 1, Protein Phosphatase 2, Protein-Serine-Threonine Kinases, Rare Diseases, Repressor Proteins, Transcription Factors, Transposases, United Kingdom, Zebrafish