Copy-Number Variation of the Glucose Transporter Gene SLC2A3 and Congenital Heart Defects in the 22q11.2 Deletion Syndrome

Mlynarski, Elisabeth E.; Sheridan, Molly B.; Xie, Michael; Guo, Tingwei; Racedo, Silvia E.; McDonald‐McGinn, Donna M.; Gai, Xiaowu; Chow, Eva W.C.; Vorstman, Jacob; Swillen, Ann; Devriendt, Koen; Breckpot, Jeroen; Digilio, María Cristina; Marino, Bruno; Dallapiccola, Bruno; Philip, Nicole; Simon, Tony J.; Roberts, Amy; Piotrowicz, Małgorzata; Bearden, Carrie E.; Eliez, Stéphan; Gothelf, Doron; Coleman, Karlene; Kates, Wendy R.; Devoto, Marcella; Zackai, Elaine H.; Heine-Suñer, Damián; Shaikh, Tamim H.; Bassett, Anne S.; Goldmuntz, Elizabeth; Morrow, Bernice E.; Emanuel, Beverly S.

doi:10.1016/j.ajhg.2015.03.007

Cited by 64 publications

(85 citation statements)

References 54 publications

(72 reference statements)

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“…Complementing the WGS approach, the study takes advantage of existing data from Affymetrix 6.0 microarrays (Figure 2) available for many participating 22q11DS subjects from previous studies of cardiac phenotypes, 83,84 with comparable array data generated for remaining subjects. Arrays provide both SNP data for use in GWAS analyses and calculation of schizophrenia polygenic scores, 85 and for genome-wide studies of structural variants (CNV) in addition to the 22q11.2 deletion.…”

Section: Genomic Approachmentioning

confidence: 99%

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A neurogenetic model for the study of schizophrenia spectrum disorders: the International 22q11.2 Deletion Syndrome Brain Behavior Consortium

et al. 2017

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Rare copy number variants contribute significantly to the risk for schizophrenia, with the 22q11.2 locus consistently implicated. Individuals with the 22q11.2 deletion syndrome (22q11DS) have an estimated 25-fold increased risk for schizophrenia spectrum disorders, compared to individuals in the general population. The International 22q11DS Brain Behavior Consortium is examining this highly informative neurogenetic syndrome phenotypically and genomically. Here we detail the procedures of the effort to characterize the neuropsychiatric and neurobehavioral phenotypes associated with 22q11DS, focusing on schizophrenia and subthreshold expression of psychosis. The genomic approach includes a combination of whole-genome sequencing and genome-wide microarray technologies, allowing the investigation of all possible DNA variation and gene pathways influencing the schizophrenia-relevant phenotypic expression. A phenotypically rich data set provides a psychiatrically well-characterized sample of unprecedented size (n = 1616) that informs the neurobehavioral developmental course of 22q11DS. This combined set of phenotypic and genomic data will enable hypothesis testing to elucidate the mechanisms underlying the pathogenesis of schizophrenia spectrum disorders.

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Section: Genomic Approachmentioning

confidence: 99%

“…2 The intact haploid 22q11.2 allele requires special computational considerations, thus is analyzed separately from data from the rest of the genome. 82,833 Annotation of structural variation from WGS data is a pioneering area of genomics. Availability of CNV data from standard microarrays in this study will be valuable for comparison purposes.…”

Section: Figurementioning

confidence: 99%

A neurogenetic model for the study of schizophrenia spectrum disorders: the International 22q11.2 Deletion Syndrome Brain Behavior Consortium

et al. 2017

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“…Current diagnostic tools include fluorescent in situ hybridization (FISH), by use of a probe for HIRA (histone cell cycle regulator, formerly TUPLE1 ) 5 located within the common deleted region, or a genome-wide comparative genomic hybridization assay that detects microdeletions of >50 kb (12). Genomic single nucleotide polymorphism arrays can also identify copy number variations in the 22q11.2 gene (13, 14). These assays require whole blood and are labor intensive and expensive to perform.…”

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confidence: 99%

MALDI-TOF-MS Assay to Detect the Hemizygous 22q11.2 Deletion in DNA from Dried Blood Spots

et al. 2016

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Background A hemizygous deletion of 1.5–3 Mb in 22q11.2 causes a distinct clinical syndrome with variable congenital defects. Current diagnostic methods use fluorescent in situ hybridization (FISH) or comparative genomic hybridization by microarray to detect the deletion. Neither method is suitable for newborn screening (NBS), since they cannot be performed on dried blood spots (DBS). We developed a MALDI-TOF-MS assay that uses DBS to measure the hemizygous deletion of UFD1L, located within the 22q11.2 region. Methods We used DBS from 54 affected patients, previously tested by FISH or microarray, and 100 cord blood samples to evaluate the performance of the MALDI-TOF-MS assay. With a single primer pair, a 97-base oligonucleotide within UFD1L was amplified, as was a sequence on chromosome 18 that differs by 2 nucleotides. A multiplexed, single-base extension reaction created allele-specific products for MALDI-TOF-MS detection. The products were spotted onto a silicon chip, and the height of the spectral peaks identified the relative amounts of target and reference gene. Results The median ratio of the spectral peak for each UFD1L target: reference base was 0.96 and 0.99 for controls, compared with 0.35 and 0.53 for 22q11 deletion syndrome patients. There was 100% concordance between FISH/micro array and MALDI-TOF-MS in all patients with 22q11.2 deletion syndrome. Conclusions This method can be reliably performed with DBS and is suitable for high sample throughput. This assay may be considered for use in population-based NBS for 22q11.2 deletion.

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“…In humans, TBX1 haploinsufficiency is the etiology responsible for 22q11DS, a clinical syndrome with a varied phenotypic spectrum, including thymic hypoplasia, congenital cardiac defects, facial dysmorphisms, velopharyngeal insufficiency with or without cleft palate and immune deficiency (20). However, an increasing number of TBX1 (54) screened TBX1 in 93 TOF probands with had no known chromosomal abnormalities or other recognized syndromes.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have established the important role genetic risk factors serve in the pathogenesis of CTD (10)(11)(12)(13)(14)(15). The 22q11 deletion syndrome (22q11DS), also known as DiGeorge syndrome, is a chromosomal abnormality responsible for ~12% of conotruncal malformations (16)(17)(18)(19)(20)(21). Furthermore, mutations in a number of genes, particularly those encoding cardiac transcriptional factors, including NKX2-5, NKX2-6, GATA4, GATA5, GATA6, PITX2, HAND2, TBX5 and TBX20, are associated with CTD .…”

Section: Introductionmentioning

confidence: 99%

TBX1 loss‑of‑function mutation contributes to congenital conotruncal defects

Zhang

Liu

et al. 2017

Exp Ther Med

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Abstract. Conotruncal defects (CTDs) account for ~30% of all types of congenital heart disease and contribute to increased morbidity and mortality rates. Increasing evidence suggests that genetic risk factors are involved in the pathogenesis of CTDs. Mutations in a number of genes, including the TBX1 gene that codes for a T-box transcription factor essential for normal cardiovascular development, may contribute to the development of CTD. CTDs are genetically heterogeneous and the genetic defects responsible for CTDs in the majority of patients remain unknown. The present study sequenced the coding regions and splicing junction boundaries of TBX1 in 136 patients with CTDs and 300 matched healthy individuals. The disease-causing potential of the identified TBX1 sequence variation was evaluated using MutationTaster, PolyPhen-2, SIFT and PROVEN software. The functional characteristics of the mutant TBX1 gene were defined using a dual-luciferase reporter assay system. A novel heterozygous TBX1 mutation, p.S233Y, was identified in a patient with transposition of the great arteries (TGA) and a ventricular septal defect. This mutation was absent in the 300 controls and altered the amino acid produced, serine, which is evolutionarily conserved across several species, and was predicted to be pathogenic in silico. Luciferase assays conducted in COS-7 cells demonstrated that the newly identified TBX1 mutation was associated with significantly diminished transcriptional activation of the ANF promoter compared with the wild-type TBX1. To the best of our knowledge, the present study is the first to associate a TBX1 loss-of-function mutation with enhanced susceptibility to TGA, which adds significant insight to the molecular mechanism of TGA.

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Copy-Number Variation of the Glucose Transporter Gene SLC2A3 and Congenital Heart Defects in the 22q11.2 Deletion Syndrome

Cited by 64 publications

References 54 publications

A neurogenetic model for the study of schizophrenia spectrum disorders: the International 22q11.2 Deletion Syndrome Brain Behavior Consortium

A neurogenetic model for the study of schizophrenia spectrum disorders: the International 22q11.2 Deletion Syndrome Brain Behavior Consortium

MALDI-TOF-MS Assay to Detect the Hemizygous 22q11.2 Deletion in DNA from Dried Blood Spots

TBX1 loss‑of‑function mutation contributes to congenital conotruncal defects

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