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

Deciphering Developmental Disorders (DDD) Study

Research output: Contribution to journalArticle (Academic Journal)peer-review

21 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)496-506
Number of pages11
JournalClinical Genetics
Issue number4
Early online date18 Mar 2019
Publication statusPublished - 1 Apr 2019

Bibliographical note

© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.


  • epilepsy
  • intellectual disability
  • IQSEC2
  • secondary microcephaly
  • twin discordance


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