De novo truncating variant in NSD2gene leading to atypical Wolf-Hirschhorn syndrome phenotype

BMC Med Genet. 2019 Aug 5;20(1):134. doi: 10.1186/s12881-019-0863-2.


Background: Wolf-Hirschhorn syndrome (WHS) is a contiguous gene syndrome caused by partial 4p deletion highly variable in size in individual patients. The core WHS phenotype is defined by the association of growth delay, typical facial characteristics, intellectual disability and seizures. The WHS critical region (WHSCR) has been narrowed down and NSD2 falls within this 200 kb region. Only four patients with NSD2 variants have been documented with phenotypic features in detail.

Case presentation: Herein, we report the case of a 12-year-old boy with developmental delay. He had dysmorphic facial features including wide-spaced eyes, prominent nasal bridge continuing to forehead, abnormal teething and micrognathia. He also had mild clinodactyly of both hands. Using whole-exome sequencing, we identified a pathogenic mutation in NSD2 [c.4029_4030insAA, p.Glu1344Lysfs*49] isolated from peripheral blood DNA. Sanger confirmation of this variant revealed it as a de novo truncating variant in the family.

Conclusion: Here, we reported a boy with de novo truncating variant in NSD2 with atypical clinical features comparing with 4p16.3 deletion related WHS. Our finding further supported the pathogenesis of truncating variants in NSD2 and delineated the possible symptom spectrum caused by these variants.

Keywords: NSD2 gene; Truncating variants; Wolf-Hirschhorn syndrome.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Child
  • Chromosomes, Human, Pair 4
  • DNA / blood
  • Developmental Disabilities / genetics
  • Exome Sequencing
  • Genetic Predisposition to Disease / genetics*
  • Histone-Lysine N-Methyltransferase / genetics*
  • Humans
  • Intellectual Disability / genetics
  • Male
  • Phenotype*
  • Repressor Proteins / genetics*
  • Seizures / genetics
  • Wolf-Hirschhorn Syndrome / genetics*
  • Wolf-Hirschhorn Syndrome / physiopathology


  • Repressor Proteins
  • DNA
  • Histone-Lysine N-Methyltransferase
  • NSD2 protein, human