Large-scale discovery of novel genetic causes of developmental disorders

Deciphering Developmental Disorders (DDD) Study

    Research output: Contribution to journalLetter

    445 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)223-228
    Number of pages6
    JournalNature
    Volume519
    Issue number7542
    DOIs
    Publication statusPublished - 12 Mar 2015

    Fingerprint Dive into the research topics of 'Large-scale discovery of novel genetic causes of developmental disorders'. Together they form a unique fingerprint.

  • Cite this

    Deciphering Developmental Disorders (DDD) Study (2015). Large-scale discovery of novel genetic causes of developmental disorders. Nature, 519(7542), 223-228. https://doi.org/10.1038/nature14135