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Region Hovedstaden - en del af Københavns Universitetshospital
Udgivet

Rare novel variants in the ZIC3 gene cause X-linked heterotaxy

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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  • Aimee D C Paulussen
  • Anja Steyls
  • Jo Vanoevelen
  • Florence Hj van Tienen
  • Ingrid P C Krapels
  • Godelieve Rf Claes
  • Sonja Chocron
  • Crool Velter
  • Gita M Tan-Sindhunata
  • Catarina Lundin
  • Irene Valenzuela
  • Balint Nagy
  • Iben Bache
  • Lisa Leth Maroun
  • Kristiina Avela
  • Han G Brunner
  • Hubert J M Smeets
  • Jeroen Bakkers
  • Arthur van den Wijngaard
Vis graf over relationer

Variants in the ZIC3 gene are rare, but have demonstrated their profound clinical significance in X-linked heterotaxy, affecting in particular male patients with abnormal arrangement of thoracic and visceral organs. Several reports have shown relevance of ZIC3 gene variants in both familial and sporadic cases and with a predominance of mutations detected in zinc-finger domains. No studies so far have assessed the functional consequences of ZIC3 variants in an in vivo model organism. A study population of 348 patients collected over more than 10 years with a large variety of congenital heart disease including heterotaxy was screened for variants in the ZIC3 gene. Functional effects of three variants were assessed both in vitro and in vivo in the zebrafish. We identified six novel pathogenic variants (1,7%), all in either male patients with heterotaxy (n=5) or a female patient with multiple male deaths due to heterotaxy in the family (n=1). All variants were located within the zinc-finger domains or leading to a truncation before these domains. Truncating variants showed abnormal trafficking of mutated ZIC3 proteins, whereas the missense variant showed normal trafficking. Overexpression of wild-type and mutated ZIC protein in zebrafish showed full non-functionality of the two frame-shift variants and partial activity of the missense variant compared with wild-type, further underscoring the pathogenic character of these variants. Concluding, we greatly expanded the number of causative variants in ZIC3 and delineated the functional effects of three variants using in vitro and in vivo model systems.

OriginalsprogEngelsk
TidsskriftEuropean journal of human genetics : EJHG
Vol/bind24
Udgave nummer12
Sider (fra-til)1783-1791
Antal sider9
ISSN1018-4813
DOI
StatusUdgivet - dec. 2016

ID: 49591514