title: Polyalanine expansion in the ZIC3 gene leading to X-linked heterotaxy with VACTERL association: a new polyalanine disorder?
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.
  
  
  CONCLUSIONS
  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.
authors.forename: Marja W
authors.initials: MW
authors.lastname: Wessels
authors.forename: Brian
authors.initials: B
authors.lastname: Kuchinka
authors.forename: Rogier
authors.initials: R
authors.lastname: Heydanus
authors.forename: Bert J
authors.initials: BJ
authors.lastname: Smit
authors.forename: Dennis
authors.initials: D
authors.lastname: Dooijes
authors.forename: Ronald R
authors.initials: RR
authors.lastname: de Krijger
authors.forename: Maarten H
authors.initials: MH
authors.lastname: Lequin
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: de Jong
authors.forename: Margreet
authors.initials: M
authors.lastname: Husen
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Willems
authors.forename: Brett
authors.initials: B
authors.lastname: Casey
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D001006:Anus, Imperforate / Q000235:genetics; D005260:Female; D050172:Genes, X-Linked; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D006330:Heart Defects, Congenital / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D010455:Peptides / Q000235:genetics*; D011247:Pregnancy; D014157:Transcription Factors / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion; D016335:Zinc Fingers / Q000235:genetics
chemical_list: D018398:Homeodomain Proteins; D010455:Peptides; D014157:Transcription Factors; C491595:ZIC3 protein, human; C019529:polyalanine