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Polyalanine expansion in the ZIC3 gene leading to X-linked heterotaxy with VACTERL association: a new polyalanine disorder?
  1. Marja W Wessels1,
  2. Brian Kuchinka2,
  3. Rogier Heydanus3,
  4. Bert J Smit4,
  5. Dennis Dooijes1,
  6. Ronald R de Krijger5,
  7. Maarten H Lequin6,
  8. Elisabeth M de Jong7,
  9. Margreet Husen8,
  10. Patrick J Willems9,
  11. Brett Casey2
  1. 1Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands
  2. 2Department of Pathology & Laboratory Medicine, University of British Columbia, and BC Children's Hospital, Vancouver, Canada
  3. 3Department of Obstetrics and Gynecology, Amphia Hospital, Breda, The Netherlands
  4. 4Department of Pediatrics, Division of Neonatology, Erasmus Medical Center, Sophia Children's Hospital, Rotterdam, The Netherlands
  5. 5Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands
  6. 6Department of Pediatric Radiology, Erasmus Medical Center, Sophia Children's Hospital, Rotterdam, The Netherlands
  7. 7Department of Pediatric Surgery, Erasmus Medical Center, Sophia Children's Hospital, Rotterdam, The Netherlands
  8. 8Department of Obstetrics and Gynecology, Erasmus Medical Center, Rotterdam, The Netherlands
  9. 9GENDIA (GENetic DIAgnostic network), Antwerp, Belgium
  1. Correspondence to Dr Marja W Wessels, Department of Clinical Genetics, Erasmus Medical Centre, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands; m.w.wessels{at}erasmusmc.nl

Abstract

Background The VACTERL association is a non-random association of congenital defects with an unknown aetiology in the majority of patients.

Methods A male newborn is reported with features of the VACTERL association, including anal atresia, laryngeal and oesophageal atresia with tracheo-oesophageal fistula, dextroposition of the heart with persistent left superior vena cava, and unilateral multicystic kidney. As the clinical picture of this patient overlaps with that of X-linked heterotaxy caused by ZIC3 mutations, the ZIC3 coding region was sequenced.

Results In a patient with the VACTERL association a 6-nucleotide insertion was found in the GCC repeat of the ZIC3 gene, which is predicted to expand the amino-terminal polyalanine repeat from 10 to 12 polyalanines. The polyalanine expansion is a novel ZIC3 mutation which was not found in 336 chromosomes from 192 ethnically matched controls. The mutation was also not present in the mother, suggesting it occurred de novo in the patient and is therefore a pathogenetic mutation.

Conclusion It is hypothesized that this novel and de novo polyalanine expansion in ZIC3 contributes to the VACTERL association in this patient.

A newborn male is described with features of the VACTERL association, including anal atresia, laryngeal and oesophageal atresia with tracheo-oesophageal fistula, dextroposition of the heart with persistent left superior vena cava, and unilateral multicystic kidney. As the clinical picture of the VACTERL association overlaps with X-linked heterotaxy caused by ZIC3 mutations, the ZIC3 coding region was sequenced, and a 6-nucleotide insertion was found that is predicted to expand the amino-terminal polyalanine repeat from 10 to 12 polyalanines. This novel mutation was not present in the mother, nor in 336 chromosomes from 192 ethnically matched controls. It is hypothesised that this novel and de novo polyalanine expansion in the ZIC3 gene contributes to the VACTERL association in this patient.

  • Congenital heart disease
  • VACTERL
  • ZIC3
  • heterotaxy
  • laryngeal atresia
  • polyalanine expansion

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Footnotes

  • Competing interests None.

  • Patient consent Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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