A study on genotypes and phenotypes of short stature caused by epigenetic modification gene variants

Eur J Pediatr. 2024 Mar;183(3):1403-1414. doi: 10.1007/s00431-023-05385-3. Epub 2024 Jan 3.


Mendelian disorders of the epigenetic machinery (MDEMs) are caused by genetic mutations, a considerable fraction of which are associated with epigenetic modification. These MDEMs exhibit phenotypic overlap broadly characterized by multiorgan abnormalities. The variant detected in genes associated with epigenetic modification can lead to short stature accompanied with multiple system abnormalities. This study is aimed at presenting and summarizing the diagnostic rate, clinical, and genetic profile of MDEMs-associated short stature. Two hundred and fourteen short-stature patients with multiorgan abnormalities were enrolled. Clinical information and whole exome sequence (WES) were analyzed for these patients. WES identified 33 pathogenic/likely pathogenic variants in 19 epigenetic modulation genes (KMT2A, KMT2D, KDM6A, SETD5, KDM5C, HUWE1, UBE2A, NIPBL, SMC1A, RAD21, CREBBP, CUL4B, BPTF, ANKRD11, CHD7, SRCAP, CTCF, MECP2, UBE3A) in 33 patients (15.4%). Of note, 19 variants had never been reported previously. Furthermore, these 33 variants were associated with 16 different disorders with overlapping clinical features characterized by development delay/intelligence disability (31/33; 93.9%), small hands (14/33; 42.4%), clinodactyly of the 5th finger (14/33; 42.4%), long eyelashes (13/33; 39.4%), and hearing impairment (9/33; 27.3%). Additionally, several associated phenotypes are reported for the first time: clubbing with KMT2A variant, webbed neck with SETD5 variant, retinal detachment with CREBBP variant, sparse lateral eyebrow with HUWE1 variant, and long palpebral fissure with eversion of the lateral third of the low eyelid with SRCAP variant.Conclusions: Our study provided a new conceptual framework for further understanding short stature. Specific clinical findings may indicate that a short-stature patient may have an epigenetic modified gene variant.

Keywords: Epigenetics; Genotypes; MDEMs; Phenotypes; Short stature.

MeSH terms

  • Abnormalities, Multiple*
  • Cell Cycle Proteins / genetics
  • Cullin Proteins / genetics
  • Epigenesis, Genetic
  • Genotype
  • Humans
  • Methyltransferases*
  • Mutation
  • Phenotype
  • Tumor Suppressor Proteins / genetics
  • Ubiquitin-Conjugating Enzymes / genetics
  • Ubiquitin-Protein Ligases / genetics


  • UBE2A protein, human
  • Ubiquitin-Conjugating Enzymes
  • NIPBL protein, human
  • Cell Cycle Proteins
  • HUWE1 protein, human
  • Tumor Suppressor Proteins
  • Ubiquitin-Protein Ligases
  • CUL4B protein, human
  • Cullin Proteins
  • SETD5 protein, human
  • Methyltransferases