Reduced Penetrance, Variable Expressivity, and Genetic Heterogeneity of Familial Atrial Septal Defects

Dw, Benson; Sharkey, Angela M.; Fatkin, D; Lang, Peter; Ct, Basson; McDonough, Barbara; Aw, Strauss; Jg, Seidman; Ce, Seidman

doi:10.1161/01.cir.97.20.2043

Cited by 87 publications

(47 citation statements)

References 25 publications

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“…Subject #27, who also had preaxial radial ray anomalies, had a personal history of congenital structural heart malformation, an interatrial septal aneurysm, and a family history of idiopathic dilated cardiomyopathy. Neither isolated interatrial septal aneurysm nor idiopathic dilated cardiomyopathy has been associated with HOS, and both have been associated with genes and/or chromosomal loci distinct from TBX5 and chromosome 12q24.1 (25,26).…”

Section: Discussionmentioning

confidence: 99%

TBX5 Genetic Testing Validates Strict Clinical Criteria for Holt-Oram Syndrome

et al. 2005

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Holt-Oram syndrome (HOS) is an autosomal dominant hearthand syndrome characterized by congenital heart disease (CHD) and upper limb deformity, and caused by mutations in the TBX5 gene. To date, the sensitivity of TBX5 genetic testing for HOS has been unclear. We now report mutational analyses of a nongenetically selected population of 54 unrelated individuals who were consecutively referred to our center with a clinical diagnosis of HOS. TBX5 mutational analyses were performed in all individuals, and clinical histories and findings were reviewed for each patient without reference to the genotypes. Twenty-six percent of the complete cohort was shown to have mutations of the TBX5 gene. However, among those subjects for whom clinical review demonstrated that their presentations met strict diagnostic criteria for HOS, TBX5 mutations were identified in 74%. No mutations were identified in those subjects who did not meet these criteria. Thus, these studies validate our clinical diagnostic criteria for HOS including an absolute requirement for preaxial radial ray upper limb malformation. Accordingly, TBX5 genotyping has high sensitivity and specificity for HOS if stringent diagnostic criteria are used in assigning the clinical diagnosis. HOS is the most common of the heart-hand syndromes. It segregates in an autosomal dominant fashion and is estimated to occur in at least 1/100,000 live births (1). HOS is characterized by upper limb anomalies involving the preaxial radial ray and CHD (2,3). Upper limb deformity may be bilateral but asymmetric or even unilateral. The most common forms of CHD associated with HOS are ASD, usually of the ostium secundum variety, and VSD, usually occurring in the muscular trabeculated septum. Cardiac conduction disease may also occur, regardless of the presence or absence of structural cardiac disease (3

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Section: Discussionmentioning

confidence: 99%

TBX5 Genetic Testing Validates Strict Clinical Criteria for Holt-Oram Syndrome

et al. 2005

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“…Most CHD occur sporadic, but in recent years an increasing number of familial cases with various types of CHD have been reported. [2][3][4] Although mutations in several genes have been identified in a small subset of patients and families with CHD, eg, NKX2.5, 2 GATA4 3 and NOTCH1, 5 the mechanisms underlying human cardiogenesis and CHDs remain largely unknown. Some CHD patients and families also display cardiac arrhythmias, which can occur due to the anatomical defect itself or sometimes due to surgical interventions.…”

Section: Introductionmentioning

confidence: 99%

A novel autosomal dominant condition consisting of congenital heart defects and low atrial rhythm maps to chromosome 9q

et al. 2011

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Congenital heart defects (CHDs) occur mostly sporadic, but familial CHD cases have been reported. Mutations in several genes, including NKX2.5, GATA4 and NOTCH1, were identified in families and patients with CHD, but the mechanisms underlying CHD are largely unknown. We performed genome-wide linkage analysis in a large four-generation family with autosomal dominant CHD (including atrial septal defect type I and II, tetralogy of Fallot and persistent left superior vena cava) and low atrial rhythm, a unique phenotype that has not been described before. We obtained phenotypic information including electrocardiography, echocardiography and DNA of 23 family members. Genome-wide linkage analysis on 12 affected, 5 unaffected individuals and 1 obligate carrier demonstrated significant linkage only to chromosome 9q21-33 with a multipoint maximum LOD score of 4.1 at marker D9S1690, between markers D9S167 and D9S1682. This 48-cM critical interval corresponds to 39 Mb and contains 402 genes. Sequence analysis of nine candidate genes in this region (INVS, TMOD1, TGFBR1, KLF4, IPPK, BARX1, PTCH1, MEGF9 and S1PR3) revealed no mutations, nor were genomic imbalances detected using array comparative genomic hybridization. In conclusion, we describe a large family with CHD and low atrial rhythm with a significant LOD score to chromosome 9q. The phenotype is representative of a mild form of left atrial isomerism or a developmental defect of the sinus node and surrounding tissue. Because the mechanisms underlying CHD are largely unknown, this study represents an important step towards the discovery of genes implied in cardiogenesis.

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“…Using previously described techniques, 14 short tandem repeat markers, including five markers from chromosome 7q34 -36 where HERG is encoded, were used to genotype participants (5).…”

Section: Methodsmentioning

confidence: 99%

Clinical, Genetic, and Biophysical Characterization of a Homozygous HERG Mutation Causing Severe Neonatal Long QT Syndrome

Johnson

Yang

et al. 2003

Pediatr Res

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Previous studies have identified mutations in five ion channel genes as a cause of long QT syndrome, a heterogeneous disorder characterized by prolongation of the QT interval, multiform ventricular tachycardia (torsades de pointes), seizures, syncope, and sudden death. However, in these studies, the average age of initial symptoms is in the third decade of life or later, and few reports have described the genetic causes of long QT syndrome presenting in the prenatal or neonatal period. We used a candidate gene approach to identify the genetic cause of long QT syndrome in an infant whose initial manifestations were detected in utero. Direct bidirectional sequencing of long QT syndrome genes identified a previously unreported HERG missense mutation (R752Q). Three asymptomatic family members were heterozygous for R752Q, and the proband, who manifested ventricular tachycardia in utero, was homozygous. R752Q was not found in 100 normal unrelated chromosomes. Paternal DNA was unavailable for testing. Transient transfection of HERG generated robust I Kr , but no current was observed for the mutant HERG. The HERG mutant, R752Q, is associated with a mild phenotype, inasmuch as family members with a heterozygous mutation appear unaffected. The homozygous mutation results in absence of functional I Kr , causing a profound loss of HERG channel function, creating the equivalent of a "HERG knockout" and leading to a severe phenotype. LQTS is a heterogeneous disorder characterized by prolongation of the QT interval, multiform ventricular tachycardia (torsades de pointes), seizures, syncope, and sudden death. Heterozygous missense mutations in the HERG gene, which encodes the ␣ subunit of a potassium channel that induces the rapid component of the delayed rectifier current, I Kr , are a common cause of LQTS (1). However, LQTS in the fetus or neonate are not reported in such studies; the initial symptoms in individuals with heterozygous HERG mutations are typically identified in older individuals, on average, in the third decade of life or later (1). We used a candidate gene approach to identify the genetic cause of LQTS in an infant whose initial manifestations were detected in utero. A previously unreported HERG mutation was identified. Family members with a heterozygous mutation had mild or absent phenotype, but the homozygous mutation resulted in a severe phenotype in the proband. METHODSClinical characteristics. The proband was referred at 38 wk gestational age for evaluation of irregular fetal heart rhythm. Echocardiographic study revealed normal cardiac structure and function. There was no atrioventricular valve regurgitation or signs of hydrops fetalis. Sinus rhythm with 1:1 atrioventricular conduction (120 beats per minute) was the predominant rhythm, but episodes of irregular fetal tachycardia (240 -250 beats per minute) were observed.

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Reduced Penetrance, Variable Expressivity, and Genetic Heterogeneity of Familial Atrial Septal Defects

Cited by 87 publications

References 25 publications

TBX5 Genetic Testing Validates Strict Clinical Criteria for Holt-Oram Syndrome

TBX5 Genetic Testing Validates Strict Clinical Criteria for Holt-Oram Syndrome

A novel autosomal dominant condition consisting of congenital heart defects and low atrial rhythm maps to chromosome 9q

Clinical, Genetic, and Biophysical Characterization of a Homozygous HERG Mutation Causing Severe Neonatal Long QT Syndrome

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