A Recurrent De Novo Nonsense Variant in ZSWIM6 Results in Severe Intellectual Disability without Frontonasal or Limb Malformations

Am J Hum Genet. 2017 Dec 7;101(6):995-1005. doi: 10.1016/j.ajhg.2017.10.009. Epub 2017 Nov 30.


A recurrent de novo missense variant within the C-terminal Sin3-like domain of ZSWIM6 was previously reported to cause acromelic frontonasal dysostosis (AFND), an autosomal-dominant severe frontonasal and limb malformation syndrome, associated with neurocognitive and motor delay, via a proposed gain-of-function effect. We present detailed phenotypic information on seven unrelated individuals with a recurrent de novo nonsense variant (c.2737C>T [p.Arg913Ter]) in the penultimate exon of ZSWIM6 who have severe-profound intellectual disability and additional central and peripheral nervous system symptoms but an absence of frontonasal or limb malformations. We show that the c.2737C>T variant does not trigger nonsense-mediated decay of the ZSWIM6 mRNA in affected individual-derived cells. This finding supports the existence of a truncated ZSWIM6 protein lacking the Sin3-like domain, which could have a dominant-negative effect. This study builds support for a key role for ZSWIM6 in neuronal development and function, in addition to its putative roles in limb and craniofacial development, and provides a striking example of different variants in the same gene leading to distinct phenotypes.

Keywords: ZSWIM6; autism; de novo; epilepsy; exome sequencing; genomics; intellectual disability; nonsense-mediated decay; recurrent; ubiquitination.

MeSH terms

  • Central Nervous System / abnormalities
  • Central Nervous System / embryology
  • Codon, Nonsense / genetics
  • DNA-Binding Proteins / genetics*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Intellectual Disability / genetics*
  • Limb Deformities, Congenital / genetics
  • Mandibulofacial Dysostosis / genetics
  • Neurocognitive Disorders / genetics*
  • Peripheral Nervous System / abnormalities
  • Peripheral Nervous System / enzymology


  • Codon, Nonsense
  • DNA-Binding Proteins
  • ZSWIM6 protein, human

Supplementary concepts

  • Acromelic Frontonasal Dysostosis