Genotype and cardiovascular phenotype correlations with TBX1 in 1,022 velo-cardio-facial/digeorge/22q11.2 deletion syndrome patients

Guo, Tingwei; McDonald‐McGinn, Donna M.; Blonska*, Anna; Shanske, Alan; Bassett, Anne S.; Chow, Eva W.C.; Bowser, Mark J.; Sheridan, Molly B.; Beemer, Frits A.; Devriendt, Koen; Swillen, Ann; Breckpot, Jeroen; Digilio, María Cristina; Marino, Bruno; Dallapiccola, Bruno; Carpenter, Courtney; Zheng, Xin; Johnson, Jacob; Chung, Jonathan; Higgins, Anne Marie; Philip, Nicole; Simon, Tony J.; Coleman, Karlene; Heine-Suñer, Damián; Rosell, Jordi; Kates, Wendy R.; Devoto, Marcella; Goldmuntz, Elizabeth; Zackai, Elaine H.; Wang, Tao; Shprintzen, Robert J.; Emanuel, Beverly S.; Morrow, Bernice E.

doi:10.1002/humu.21568

Cited by 64 publications

(63 citation statements)

References 70 publications

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“…Owing to the complexity of LCRs 229 , the rearrangement breakpoints and sequences driving non-allelic homologous recombination remain uncharted. Even the latest human genome assembly (GRCh38) contains gaps in the LCRs of the 22q11.2 region 59,60 .…”

Section: Discussionmentioning

confidence: 99%

22q11.2 deletion syndrome

McDonald‐McGinn

Sullivan

Marino

et al. 2015

Nat Rev Dis Primers

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22q11.2 deletion syndrome (22q11.2DS) is the most common chromosomal microdeletion disorder, estimated to result mainly from de novo non-homologous meiotic recombination events occurring in approximately 1 in every 1,000 fetuses. The first description in the English language of the constellation of findings now known to be due to this chromosomal difference was made in the 1960s in children with DiGeorge syndrome, who presented with the clinical triad of immunodeficiency, hypoparathyroidism and congenital heart disease. The syndrome is now known to have a heterogeneous presentation that includes multiple additional congenital anomalies and later-onset conditions, such as palatal, gastrointestinal and renal abnormalities, autoimmune disease, variable cognitive delays, behavioural phenotypes and psychiatric illness — all far extending the original description of DiGeorge syndrome. Management requires a multidisciplinary approach involving paediatrics, general medicine, surgery, psychiatry, psychology, interventional therapies (physical, occupational, speech, language and behavioural) and genetic counselling. Although common, lack of recognition of the condition and/or lack of familiarity with genetic testing methods, together with the wide variability of clinical presentation, delays diagnosis. Early diagnosis, preferably prenatally or neonatally, could improve outcomes, thus stressing the importance of universal screening. Equally important, 22q11.2DS has become a model for understanding rare and frequent congenital anomalies, medical conditions, psychiatric and developmental disorders, and may provide a platform to better understand these disorders while affording opportunities for translational strategies across the lifespan for both patients with 22q11.2DS and those with these associated features in the general population.

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Section: Discussionmentioning

confidence: 99%

22q11.2 deletion syndrome

McDonald‐McGinn

Sullivan

Marino

et al. 2015

Nat Rev Dis Primers

Self Cite

1,030

1,133

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“…Thus far, SNP analyses of TBX1 in humans have failed to identify positive associations with the 22q11DS cardiac or cleft palate phenotypes. 19,20 Catechol-O-methyltransferase (COMT ), also deleted in 22q11DS, functions in degrading catecholamines and thus is a candidate for many neurological 22q11DS phenotypes. A valine-to-methionine substitution at codon 158 (COMT Val158Met) results in a form of COMT with decreased enzymatic activity; the presence of this allele in the non-deleted chromosome may further enhance the effects of COMT haploinsufficiency caused by the deletion.…”

Section: Introductionmentioning

confidence: 99%

Implications of COMT long-range interactions on the phenotypic variability of 22q11.2 deletion syndrome

Zeitz

Lerner

et al. 2013

Nucleus

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“…The most common association with persistent truncus arteriosus (PTA) is 22q11 deletion syndrome, with deletion of TBX1 being the most common gene deletion associated with PTA in the syndrome. (28) There have been preliminary studies that link variations in the remaining copy of TBX1 with the presence of CHD in patients with 22q11 deletions. Several mouse models of PTA have been developed.…”

Section: Conotruncal Defectsmentioning

confidence: 99%

Genetic Basis of Congenital Heart Disease

Morton

Roberts

2015

NeoReviews

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1. Knowing the various genetic causes of congenital heart disease, including nonprotein coding elements, will help when assessing patients and families for comorbidities and recurrence of congenital heart disease. 2. Understanding the indications and methods for genetic testing in congenital heart disease will improve appropriate application of such testing in the neonatal intensive care unit. AbstractThe heart is the first organ to function during mammalian development. Cardiac morphogenesis is a carefully orchestrated process that involves numerous transcription factors and signaling pathways. Our understanding of the genetic factors important for cardiac development has progressed significantly during the past 2 decades, and it is possible to identify a genetic cause for an increasing number of patients with syndromic and nonsyndromic congenital heart disease. This review discusses the genes important in heart development and current techniques for evaluating possible genetic causes in neonatal intensive care unit patients.Objectives After completing this article, the reader should be able to:1. Describe the process of cardiac development. 2. Identify common genes involved in congenital heart disease. 3. Recognize the indications and limitations of current genetic testing. Epidemiology of Congenital Heart DiseaseThe incidence of congenital heart disease (CHD) is estimated at 6 to 12 per 1,000 live births. A study in Quebec identified a 19% increase in the prevalence of severe CHD from 2000 to 2010 compared with an increase in overall CHD by 11%, indicating increasing survival for the most severely affected patients.(1) True prevalence is likely higher because mild CHD, such as bicuspid aortic valve, is often not detected until later in life, if at all. Modern diagnostic testing approaches have increased the proportion of patients with CHD who have an identified underlying genetic abnormality. Studies have detected chromosomal anomalies in 36% of patients with CHD, microdeletions and genetic syndromes in 5% to 10%, and teratogens as a cause in less than 1%.(2) There is variable but strong familial clustering of CHD. Modeling has suggested that there is a functional convergence of factors that lead to CHD, meaning that separate risk factors combine to cause CHD by targeting different molecules involved in final common pathways for cardiac development. Maternal FactorsBecause the critical period for human cardiac development is 2 to 7 weeks' gestation, maternal risk factors associated with structural CHD must be present before the end of the first trimester. Other conditions, such a cardiomyopathy or arrhythmia, can develop later in gestation. One of the best known factors associated with a decreased rate of CHD is folic acid

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Genotype and cardiovascular phenotype correlations with TBX1 in 1,022 velo-cardio-facial/digeorge/22q11.2 deletion syndrome patients

Cited by 64 publications

References 70 publications

22q11.2 deletion syndrome

22q11.2 deletion syndrome

Implications of COMT long-range interactions on the phenotypic variability of 22q11.2 deletion syndrome

Genetic Basis of Congenital Heart Disease

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