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Author Notes:

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@mcgill.ca

DMM-M and SF contributed equally to this work.

For a complete list of author contributions, please see the full work.

We would like to acknowledge Patrick McMahon MD for his help in assessing and documenting the dermatologic findings in patients 1 and 2; Elizabeth Bratton for assistance with clinical data collection in the ‘22q and You’ Center; Piotr Jurgielewicz for assistance with gathering reference materials; Colleen Franconi for technical assistance in the laboratory of Dr Beverly S Emanuel, all at the Children's Hospital of Philadelphia.

We also wish to acknowledge the contribution of the high-throughput sequencing platform of the McGill University and Genome Québec Innovation Centre (Montréal, Canada) and Dr Jacek Majewski for his help in analysing the exome data.


Research Funding:

This work was supported by a grant from the Canadian Institutes of Health Research (#MOP-102666) to LJM, and NIH support (HL84410, MH87636 and HD070454) to BSE, DMM-M and EHZ.

BAN is supported by KOLUMB fellowship from the Foundation for Polish Science.

The Charles EH Upham Chair to BSE provided funds for this research at the Children's Hospital of Philadelphia.

JV was supported by the Jerome Lejeune Foundation and LJM is a member of the Research Institute of the McGill University Health Centre, which is supported in part by the FRSQ.


  • Science & Technology
  • Life Sciences & Biomedicine
  • Genetics & Heredity
  • 22q11.2DS
  • SNAP29
  • Kousseff
  • Exome Sequencing

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

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Journal Title:

Journal of Medical Genetics


Volume 50, Number 2


, Pages 80-90

Type of Work:

Article | Final Publisher PDF


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.

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Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions

This is an Open Access work distributed under the terms of the Creative Commons Attribution-Noncommercial 3.0 Unported License (http://creativecommons.org/licenses/by-nc/3.0/).

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