title: Hemizygous mutations in SNAP29 unmask autosomal recessive conditions and contribute to atypical findings in patients with 22q11.2DS.
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.
  
  
  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.
authors.affiliation: Division of Human Genetics, The Children’s Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Donna M
authors.initials: DM
authors.lastname: McDonald-McGinn
authors.forename: Somayyeh
authors.initials: S
authors.lastname: Fahiminiya
authors.forename: Timothée
authors.initials: T
authors.lastname: Revil
authors.forename: Beata A
authors.initials: BA
authors.lastname: Nowakowska
authors.forename: Joshua
authors.initials: J
authors.lastname: Suhl
authors.forename: Alice
authors.initials: A
authors.lastname: Bailey
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Mlynarski
authors.forename: David R
authors.initials: DR
authors.lastname: Lynch
authors.forename: Albert C
authors.initials: AC
authors.lastname: Yan
authors.forename: Larissa T
authors.initials: LT
authors.lastname: Bilaniuk
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Sullivan
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Warren
authors.forename: Beverly S
authors.initials: BS
authors.lastname: Emanuel
authors.forename: Joris R
authors.initials: JR
authors.lastname: Vermeesch
authors.forename: Elaine H
authors.initials: EH
authors.lastname: Zackai
authors.forename: Loydie A
authors.initials: LA
authors.lastname: Jerome-Majewska
mesh_terms: D002874:Chromosome Mapping; D015331:Cohort Studies; D004062:DiGeorge Syndrome / Q000235:genetics* / Q000473:pathology; D059472:Exome; D005260:Female; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D050766:Qb-SNARE Proteins / Q000235:genetics*; D050767:Qc-SNARE Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D050766:Qb-SNARE Proteins; D050767:Qc-SNARE Proteins; C432420:SNAP29 protein, human