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J Med Genet doi:10.1136/jmedgenet-2012-101320
  • Genotype—phenotype correlations
  • Original article

Hemizygous mutations in SNAP29 unmask autosomal recessive conditions and contribute to atypical findings in patients with 22q11.2DS

Open Access
  1. Loydie A Jerome-Majewska2,11
  1. 1Division of Human Genetics, The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
  2. 2Department of Human Genetics, McGill University, Montreal, Quebec, Canada
  3. 3Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland
  4. 4Department of Human Genetics, Emory University School of Medicine, Atlanta, USA
  5. 5Departments of Neurology and Pediatrics, The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
  6. 6Division of Dermatology, The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
  7. 7Division of Neuroradiology, The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
  8. 8Division of Allergy Immunology, The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
  9. 9Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
  10. 10Center for Human Genetics, Catholic University Leuven, University Hospital Gasthuisberg, Leuven, Belgium
  11. 11Department of Pediatrics, McGill University, Montreal Children's Hospital, Montreal, Quebec, Canada
  1. Correspondence to Dr Loydie A Jerome-Majewska, Department of Pediatrics and Human Genetics, McGill University Research Institute, Place Toulon, 4060 Ste Catherine West PT 420, Montreal, QC H3Z 2Z3, Canada; loydie.majewska{at}mcgill.ca
  • Received 24 September 2012
  • Revised 10 November 2012
  • Accepted 13 November 2012
  • Published Online First 11 December 2012

Abstract

Background 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion disorder, affecting an estimated 1 : 2000–4000 live births. Patients with 22q11.2DS have a broad spectrum of phenotypic abnormalities which generally includes congenital cardiac abnormalities, palatal anomalies, and immunodeficiency. Additional findings, such as skeletal anomalies and autoimmune disorders, can confer significant morbidity in a subset of patients. 22q11.2DS is a contiguous gene DS and over 40 genes are deleted in patients; thus deletion of several genes within this region contributes to the clinical features. Mutations outside or on the remaining 22q11.2 allele are also known to modify the phenotype.

Methods We utilised whole exome, targeted exome and/or Sanger sequencing to examine the genome of 17 patients with 22q11.2 deletions and phenotypic features found in <10% of affected individuals.

Results and conclusions In four unrelated patients, we identified three novel mutations in SNAP29, the gene implicated in the autosomal recessive condition cerebral dysgenesis, neuropathy, ichthyosis and keratoderma (CEDNIK). SNAP29 maps to 22q11.2 and encodes a soluble SNARE protein that is predicted to mediate vesicle fusion at the endoplasmic reticulum or Golgi membranes. This work confirms that the phenotypic variability observed in a subset of patients with 22q11.2DS is due to mutations on the non-deleted chromosome, which leads to unmasking of autosomal recessive conditions such as CEDNIK, Kousseff, and a potentially autosomal recessive form of Opitz G/BBB syndrome. Furthermore, our work implicates SNAP29 as a major modifier of variable expressivity in 22q11.2 DS patients.

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