Deep phenotyping of 14 new patients with IQSEC2 variants, including monozygotic twins of discordant phenotype

Clin Genet. 2019 Apr;95(4):496-506. doi: 10.1111/cge.13507.


Whole-exome sequencing has established IQSEC2 as a neurodevelopmental disability gene. The IQSEC2 variant phenotype includes developmental delay, intellectual disability, epilepsy, hypotonia, autism, developmental regression, microcephaly and stereotypies but is yet to be fully described. Presented here are 14 new patients with IQSEC2 variants. In addition to the established features, we observed: gait ataxia in 7 of 9 (77.8%), drooling in 9 of 14 (64.2%), early feeding difficulties in 7 of 14 (50%), structural brain abnormalities in 6 of 13 (46.2%), brachycephaly in 5 of 14 (35.7%), and scoliosis and paroxysms of laughter each in 4 of 14 (28.6%). We suggest that these are features of the IQSEC2-related disorder. Gastrostomy requirement, plagiocephaly, strabismus and cortical blindness, each seen in 2 of 14 (14.3%), may also be associated. Shared facial features were noted in 8 of 14 patients, and shared hair patterning was identified in 5 of 14 patients. This study further delineates the IQSEC2 phenotypic spectrum and supports the notion of an emerging IQSEC2 syndrome. We draw parallels between the IQSEC2-related disorder and the Angelman-/Rett-/Pitt-Hopkins syndrome group of conditions and recommend the addition of IQSEC2 to epilepsy and developmental delay gene panels. We observed discordant phenotypes in monozygotic twins and apparent gonadal mosaicism, which has implications for recurrence risk counselling in the IQSEC2-related disorder.

Keywords: IQSEC2; epilepsy; intellectual disability; secondary microcephaly; twin discordance.

Publication types

  • Research Support, Non-U.S. Gov't
  • Twin Study

MeSH terms

  • Alleles
  • Amino Acid Substitution
  • Child
  • Child, Preschool
  • Facies
  • Female
  • Genetic Association Studies* / methods
  • Genetic Predisposition to Disease*
  • Genetic Variation*
  • Guanine Nucleotide Exchange Factors / genetics*
  • Humans
  • Infant
  • Male
  • Phenotype*
  • Twins, Monozygotic / genetics*
  • Whole Exome Sequencing


  • Guanine Nucleotide Exchange Factors
  • IQSEC2 protein, human