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Hemizygous Mutations in SNAP29 Unmask Autosomal Recessive

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Hemizygous Mutations in SNAP29 Unmask Autosomal Recessive JMG Online First, published on December 11, 2012 as 10.1136/jmedgenet-2012-101320 Genotype—phenotype correlations J Med Genet: first published as 10.1136/jmedgenet-2012-101320 on 11 December 2012. Downloaded from ORIGINAL ARTICLE Hemizygous mutations in SNAP29 unmask autosomal recessive conditions and contribute to atypical findings in patients with 22q11.2DS Donna M McDonald-McGinn,1 Somayyeh Fahiminiya,2 Timothée Revil,2 Beata A Nowakowska,3 Joshua Suhl,4 Alice Bailey,1 Elisabeth Mlynarski,1 David R Lynch,5 Albert C Yan,6 Larissa T Bilaniuk,7 Kathleen E Sullivan,8 Stephen T Warren,4 Beverly S Emanuel,1,9 Joris R Vermeesch,10 Elaine H Zackai,1,9 Loydie A Jerome-Majewska2,11 ▸ Additional supplementary ABSTRACT the architecture of chromosome 22q11.2 and are data are published online only. Background 22q11.2 deletion syndrome (22q11.2DS) associated with a non-allelic homologous recombin- To view these files please visit is the most common microdeletion disorder, affecting an ation between chromosome specific low copy repeats the journal online (http://dx. 3 doi.org/10.1136/jmedgenet- estimated 1 : 2000–4000 live births. Patients with (LCRs) or segmental duplications. The larger 3 MB 2012-101320). 22q11.2DS have a broad spectrum of phenotypic deletion is associated with recombination between For numbered affiliations see abnormalities which generally includes congenital cardiac LCRs-A and D. Furthermore, although the smaller end of article abnormalities, palatal anomalies, and immunodeficiency. atypical nested deletions are predominantly mediated Additional findings, such as skeletal anomalies and by LCRs A-B, they also include deletions involving Correspondence to autoimmune disorders, can confer significant morbidity LCRs B-D or C-D. In general, the associated clinical Dr Loydie A Jerome-Majewska, fi Department of Pediatrics and in a subset of patients. 22q11.2DS is a contiguous gene ndings include: congenital cardiac abnormalities, Human Genetics, McGill DS and over 40 genes are deleted in patients; thus palatal anomalies, and immunodeficiency in about University Research Institute, deletion of several genes within this region contributes three-quarters of patients; hypoparathyroidism in Place Toulon, 4060 Ste to the clinical features. Mutations outside or on the approximately half; and gastrointestinal and renal – Catherine West PT 420, remaining 22q11.2 allele are also known to modify the anomalies in about one-third.4 6 Additional findings Montreal, QC H3Z 2Z3, fi Canada; phenotype. can confer signi cant morbidity, such as autoimmune [email protected] Methods We utilised whole exome, targeted exome disease and skeletal anomalies, but are generally iden- and/or Sanger sequencing to examine the genome of 17 tified in only a subset of patients.7 Lastly, develop- DMM-M and SF contributed patients with 22q11.2 deletions and phenotypic features mental delay, intellectual deficits, and psychiatric equally to this work found in <10% of affected individuals. disorders such as schizophrenia are important fea- 8 Received 24 September 2012 Results and conclusions In four unrelated patients, turesofthisdiagnosis. http://jmg.bmj.com/ Revised 10 November 2012 we identified three novel mutations in SNAP29, the gene Although as many as 40 genes are deleted in Accepted 13 November 2012 implicated in the autosomal recessive condition cerebral patients with 22q11.2DS, mouse models of dysgenesis, neuropathy, ichthyosis and keratoderma 22q11.2DS support a strong role for haploinsuffi- (CEDNIK). SNAP29 maps to 22q11.2 and encodes a ciency of TBX1, a T-Box gene in the A-B deleted soluble SNARE protein that is predicted to mediate region. TBX1 has been implicated in association vesicle fusion at the endoplasmic reticulum or Golgi with several clinical findings, in particular congeni- 9 membranes. This work confirms that the phenotypic tal heart disease. In patients with atypical deletions on September 26, 2021 by guest. Protected copyright. variability observed in a subset of patients with that do not include TBX1, the adaptor protein 22q11.2DS is due to mutations on the non-deleted CRKL has emerged as a strong candidate for add- chromosome, which leads to unmasking of autosomal itional associated features.10 In addition, a signifi- recessive conditions such as CEDNIK, Kousseff, and a cant number of patients with 22q11.2DS have less potentially autosomal recessive form of Opitz G/BBB common findings such as polymicrogyria, myelo- syndrome. Furthermore, our work implicates SNAP29 as meningocele, cleft lip, and genitourinary abnormal- a major modifier of variable expressivity in 22q11.2 DS ities that cannot be explained solely by patients. haploinsufficiency for TBX1 and/or CRKL. However, 22q11.2DS is considered a contiguous gene deletion syndrome as it has been proposed INTRODUCTION that loss of several or all genes within the region Although clinically under-recognised, the 22q11.2 may contribute to the broad phenotype observed in deletion syndrome (22q11.2DS) is the most common patients.11 microdeletion disorder with an estimated prevalence Next-generation sequencing advances, such as To cite: McDonald- of 1 in 2000–4000 live births. Individuals with whole exome sequencing, enables identification of McGinn DM, Fahiminiya S, et al J Med 22q11.2DS most often have a classically associated rare variants that may be damaging and therefore Revil Tée, . 12 Genet Published Online First: 3 MB deletion. However, smaller atypical nested disease producing. This new technology permits 10 December 2012 deletions have been reported, all of which result in a examination of the genome including the non- doi:10.1136/jmedgenet- broad spectrum of phenotypic abnormalities.12The deleted allele for mutations that may contribute to 2012-101320 occurrences of deletions in this region are related to variable phenotypic expression in deletion McDonald-McGinnCopyright DM,Articleet al. J author Med Genet (or2012; their0:1–11. employer) doi:10.1136/jmedgenet-2012-101320 2012. Produced by BMJ Publishing Group Ltd under licence. 1 Genotype—phenotype correlations J Med Genet: first published as 10.1136/jmedgenet-2012-101320 on 11 December 2012. Downloaded from syndromes. Thus, we utilised whole or targeted exome sequen- discarded in further analyses. A mean coverage of 66X (patient cing in patients with a 22q11.2 deletion and phenotypic features 1), 91X (patient 5), 78X (patient 6), and 76X (patient 7) was found in <10% of affected individuals and identified damaging obtained for all consensus coding sequence exons. mutations in SNAP29, the gene implicated in the autosomal The variant positions on the reference genome were determined recessive condition cerebral dysgenesis, neuropathy, ichthyosis using Samtools (v.0.1.17),22 mpileup and varFilter with the base and keratoderma (CEDNIK).13 14 SNAP29 is located within the alignment quality adjustment disabled, leading to the identification C-D region on chromosome 22q11.2. Heterozygous mutations of approximately 299K (patient 1), 286K (patient 5), 265K of SNAP29 have also been reported in association with crypt- (patient 6), and 269K (patient 7) variants. Additional filters were orchidism and hypospadias.15 Furthermore, single nucleotide applied to narrow down the list of candidate rare variants. First, a polymorphisms (SNPs) in the promoter of SNAP29 have been minimum of two variant reads and >20% single nucleotide var- associated with schizophrenia.16 iants or >15% indels (small insertions or deletions) variant reads SNAP29 (synaptosomal associated protein 29KDa) is a were considered for each called position. In order to remove sys- soluble SNARE protein that is predicted to mediate vesicle tematic false positives and common polymorphisms, the variants fusion at the endoplasmic reticulum or Golgi membranes.17 were filtered against our in-house exome database (>350 exomes) SNAP29 was shown to be highly expressed in myelinating glia18 and removed from further analysis if seen in more than five and is required for lamellar body formation in the skin. It is control exomes. also indirectly required for β1 integrin endocytosis and cell Subsequently, ANNOVAR23 was used to annotate the remain- migration.19 We report that hemizygous deletions of 22q11.2, ing variants according to the type of mutation, whether the combined with damaging mutations in SNAP29, contribute to variant was present in dbSNP132, minor allele frequency in the atypical clinical findings in patients with 22q11.2DS. 1000 Genomes project, exome variant server (EVS), SIFT, Specifically, this combination unmasks one previously described PolyPhen-2 and PHASTCONS scores. Based on the assumption autosomal recessive condition (CEDNIK), and may unmask and that the potential damaging variants are rare, the variants were confirm another condition previously debated in the literature kept in the final list if they had an allele frequency <0.05 in the (Kousseff syndrome). It also may provide an explanation for 1000 Genomes database and predicted to be non-synonymous, overlapping features with a third heterogeneous condition that is, missense, nonsense, frameshift, or canonical splice site (Opitz G/BBB syndrome). changes. A summary of the data obtained from each step of exome sequencing analysis is presented in supplementary table 1. PATIENTS AND METHODS The study was approved by the Institutional Review Board of Targeted exome sequencing and analysis the Children’s Hospital of Philadelphia (07-005352) with The mutation in patient 4 was identified using a custom Agilent appropriate informed consent
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