KBG syndrome involving a single-nucleotide duplication in ANKRD11

Cold Spring Harb Mol Case Stud. 2016 Nov;2(6):a001131. doi: 10.1101/mcs.a001131.


KBG syndrome is a rare autosomal dominant genetic condition characterized by neurological involvement and distinct facial, hand, and skeletal features. More than 70 cases have been reported; however, it is likely that KBG syndrome is underdiagnosed because of lack of comprehensive characterization of the heterogeneous phenotypic features. We describe the clinical manifestations in a male currently 13 years of age, who exhibited symptoms including epilepsy, severe developmental delay, distinct facial features, and hand anomalies, without a positive genetic diagnosis. Subsequent exome sequencing identified a novel de novo heterozygous single base pair duplication (c.6015dupA) in ANKRD11, which was validated by Sanger sequencing. This single-nucleotide duplication is predicted to lead to a premature stop codon and loss of function in ANKRD11, thereby implicating it as contributing to the proband's symptoms and yielding a molecular diagnosis of KBG syndrome. Before molecular diagnosis, this syndrome was not recognized in the proband, as several key features of the disorder were mild and were not recognized by clinicians, further supporting the concept of variable expressivity in many disorders. Although a diagnosis of cerebral folate deficiency has also been given, its significance for the proband's condition remains uncertain.

Keywords: absent speech; autism; bilateral single transverse palmar creases; broad nasal tip; clinodactyly of the 5th finger; developmental regression; generalized tonic–clonic seizures on awakening; intellectual disability, moderate; low CSF 5-methyltetrahydrofolate; pes planus; short philtrum; short toe.

Publication types

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

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Adolescent
  • Bone Diseases, Developmental / genetics*
  • Chromosome Deletion
  • Chromosomes, Human, Pair 16 / genetics
  • Exome Sequencing / methods
  • Facies
  • Heterozygote
  • Humans
  • Intellectual Disability / genetics*
  • Male
  • Nucleotides / genetics
  • Pedigree
  • Phenotype
  • Repressor Proteins / genetics*
  • Repressor Proteins / metabolism
  • Tooth Abnormalities / genetics*


  • ANKRD11 protein, human
  • Nucleotides
  • Repressor Proteins

Supplementary concepts

  • KBG syndrome