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

• Authors: Donna M. McDonald-McGinn, University of Pennsylvania; Somayyeh Fahiminiya, McGill University; Timothee Revil, McGill University; Beata A. Nowakowska, Institute of Mother and Child; Joshua Suhl, Emory University; Alice Bailey, University of Pennsylvania; Elisabeth Mlynarski, University of Pennsylvania; David R. Lynch, University of Pennsylvania; Albert C. Yan, University of Pennsylvania; Larissa T. Bilaniuk, University of Pennsylvania; Kathleen E. Sullivan, University of Pennsylvania; Stephen Warren, Emory University; Beverly S. Emanuel, University of Pennsylvania; Joris R. Vermeesch, University Hospital Gasthuisberg; Elaine H. Zackai, University of Pennsylvania; Loydie A. Jerome-Majewska, McGill University
• Journal Title: Journal of Medical Genetics
• Volume: Volume 50, Number 2
• Publisher: BMJ Publishing Group | 2013-02, Pages 80-90
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1136/jmedgenet-2012-101320
• Subjects: Biology, Genetics; Biology, Neuroscience
• Keywords: Science & Technology; Life Sciences & Biomedicine; Genetics & Heredity; GENETICS & HEREDITY; OPITZ GBBB SYNDROME; BERNARD-SOULIER SYNDROME; DIGEORGE-SYNDROME; DELETION SYNDROME; KOUSSEFF-SYNDROME; REGION; IDENTIFICATION; PHENOTYPE; DEFECTS; GENES; 22q11.2DS; SNAP29; CEDNIK; Kousseff; Exome Sequencing

Abstract

Background: 22q11.12 deletion syndrome (22q11.12DS) is the most common microdeletion disorder, affecting an estimated 1 : 2000-4000 live births. Patients with 22q11.12DS 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. 22q11.12DS 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 22q11.12 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 22q11.12 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 22q11.12 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 22q11.12DS 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 22q11.12 DS patients.