Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families

Nat Genet. 2015 Nov;47(11):1363-9. doi: 10.1038/ng.3410. Epub 2015 Oct 5.


Discovery of most autosomal recessive disease-associated genes has involved analysis of large, often consanguineous multiplex families or small cohorts of unrelated individuals with a well-defined clinical condition. Discovery of new dominant causes of rare, genetically heterogeneous developmental disorders has been revolutionized by exome analysis of large cohorts of phenotypically diverse parent-offspring trios. Here we analyzed 4,125 families with diverse, rare and genetically heterogeneous developmental disorders and identified four new autosomal recessive disorders. These four disorders were identified by integrating Mendelian filtering (selecting probands with rare, biallelic and putatively damaging variants in the same gene) with statistical assessments of (i) the likelihood of sampling the observed genotypes from the general population and (ii) the phenotypic similarity of patients with recessive variants in the same candidate gene. This new paradigm promises to catalyze the discovery of novel recessive disorders, especially those with less consistent or nonspecific clinical presentations and those caused predominantly by compound heterozygous genotypes.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Proteins / genetics
  • Developmental Disabilities / classification
  • Developmental Disabilities / genetics*
  • Exome / genetics
  • Family Health
  • Female
  • Genes, Recessive*
  • Genetic Association Studies / methods*
  • Genetic Predisposition to Disease / genetics*
  • Genetic Variation
  • Genotype
  • Humans
  • Male
  • Matrix Metalloproteinases, Secreted / genetics
  • Pedigree
  • Phenotype
  • Protein-Arginine N-Methyltransferases / genetics
  • Sequence Analysis, DNA / methods
  • Ubiquitin-Protein Ligases / genetics
  • United Kingdom


  • Cell Cycle Proteins
  • KIAA0586 protein, human
  • PRMT7 protein, human
  • Protein-Arginine N-Methyltransferases
  • HACE1 protein, human
  • Ubiquitin-Protein Ligases
  • MMP21 protein, human
  • Matrix Metalloproteinases, Secreted