Biallelic variants in DNA2 cause microcephalic primordial dwarfism

Hum Mutat. 2019 Aug;40(8):1063-1070. doi: 10.1002/humu.23776. Epub 2019 Jun 23.


Microcephalic primordial dwarfism (MPD) is a group of rare single-gene disorders characterized by the extreme reduction in brain and body size from early development onwards. Proteins encoded by MPD-associated genes play important roles in fundamental cellular processes, notably genome replication and repair. Here we report the identification of four MPD individuals with biallelic variants in DNA2, which encodes an adenosine triphosphate (ATP)-dependent helicase/nuclease involved in DNA replication and repair. We demonstrate that the two intronic variants (c.1764-38_1764-37ins(53) and c.74+4A>C) found in these individuals substantially impair DNA2 transcript splicing. Additionally, we identify a missense variant (c.1963A>G), affecting a residue of the ATP-dependent helicase domain that is highly conserved between humans and yeast, with the resulting substitution (p.Thr655Ala) predicted to directly impact ATP/ADP (adenosine diphosphate) binding by DNA2. Our findings support the pathogenicity of these variants as biallelic hypomorphic mutations, establishing DNA2 as an MPD disease gene.

Keywords: DNA repair; DNA replication; DNA2; growth; microcephalic primordial dwarfism.

Publication types

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

MeSH terms

  • Adolescent
  • Alleles
  • DNA Helicases / chemistry
  • DNA Helicases / genetics*
  • Dwarfism / genetics*
  • Female
  • Genetic Predisposition to Disease
  • Genetic Variation*
  • Humans
  • Introns
  • Male
  • Microcephaly / genetics*
  • Middle Aged
  • Models, Molecular
  • Mutagenesis, Insertional
  • Mutation, Missense
  • Polymorphism, Single Nucleotide


  • DNA Helicases
  • DNA2 protein, human