GeneMatcher Aids in the Identification of a New Malformation Syndrome With Intellectual Disability, Unique Facial Dysmorphisms, and Skeletal and Connective Tissue Abnormalities Caused by De Novo Variants in HNRNPK

Hum Mutat. 2015 Oct;36(10):1009-1014. doi: 10.1002/humu.22837. Epub 2015 Aug 6.


We report a new syndrome due to loss-of-function variants in the heterogeneous nuclear ribonucleoprotein K gene (HNRNPK). We describe two probands: one with a de novo frameshift (NM_002140.3: c.953+1dup), and the other with a de novo splice donor site variant (NM_002140.3: c.257G>A). Both probands have intellectual disability, a shared unique craniofacial phenotype, and connective tissue and skeletal abnormalities. The identification of this syndrome was made possible by a new online tool, GeneMatcher, which facilitates connections between clinicians and researchers based on shared interest in candidate genes. This report demonstrates that new Web-based approaches can be effective in helping investigators solve exome sequencing projects, and also highlights the newer paradigm of "reverse phenotyping," where characterization of syndromic features follows the identification of genetic variants.

Keywords: GeneMatcher; HNRNPK; WES; matchmaker exchange; reverse phenotyping.

Publication types

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

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Adolescent
  • Child
  • Craniofacial Abnormalities / genetics*
  • Databases, Genetic*
  • Genetic Predisposition to Disease
  • Heterogeneous-Nuclear Ribonucleoprotein K
  • Humans
  • Information Dissemination
  • Intellectual Disability / genetics*
  • Male
  • Muscular Atrophy / genetics*
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Ribonucleoproteins / genetics*
  • Software
  • Web Browser


  • Heterogeneous-Nuclear Ribonucleoprotein K
  • Ribonucleoproteins
  • HNRNPK protein, human

Supplementary concepts

  • Facial Dysmorphism with Multiple Malformations