Holt–Oram syndrome is a genetically heterogeneous disease with one locus mapping to human chromosome 12q

Ja, Terrett; Newbury‐Ecob, Ruth; Gs, Cross; Fenton, I.; Raeburn, J. A.; Young, I.D.; Brook, David

doi:10.1038/ng0494-401

Cited by 82 publications

(35 citation statements)

References 9 publications

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“…In 1994 the gene locus for HOS was mapped to chromosome 12q24.1 and in 1997 germline mutations within the TBX5 gene were identified to cause the Holt-Oram syndrome (Terrett et al, 1994;Basson et al, 1995Basson et al, , 1997Li et al, 1997). TBX5 is a member of the T-box transcription factor family and it plays a major role in the development of the heart and upper limbs during embryogenesis.…”

Section: Introductionmentioning

confidence: 99%

The human TBX5 gene mutation database

et al. 2005

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Germline mutations of the TBX5 gene were identified as the primary cause in up to 70 % of patients with Holt-Oram syndrome (HOS), an autosomal dominant disorder characterized by malformations of the upper limbs and cardiac defects. Furthermore, somatic mutations of the TBX5 gene have been described in diseased heart tissues of patients with congenital heart defects of different cause. The relationship between genotype and phenotype remains unclear and the underlying mechanism of the pathogenic effect is not solved. In this report, we introduce the 'TBX5 Gene Mutation Database,' an online locus specific database containing germline and somatic mutations of the TBX5 gene. The permanently updated data collection includes all reported mutations beginning with the first description of the gene in 1997. With our database we complement the existing resources by: 1) giving a complete review of the so far reported mutation spectrum in TBX5 considering the clinical relevance; 2) linkage of the mutational data to the corresponding gene location and PubMedAbstracts; and 3) additional links to other related resources like SNP database, sequences and literature references. The usage of our database will help to quickly find informations about genetic variations within the TBX5 gene. Here we describe the database structure, content, and potential applications (http://www.uni-leipzig.de/∼genetik/TBX5).

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Section: Introductionmentioning

confidence: 99%

The human TBX5 gene mutation database

et al. 2005

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Section: (Pediatr Res 58: 981-986 2005)mentioning

confidence: 99%

“…Genetic heterogeneity of HOS has been controversial (17)(18)(19). Although linkage to the TBX5 chromosome 12q24.1 locus has been the rule, genetic heterogeneity has been proposed in three families (17)(18)(19). However, of these families, one exhibited polydactyly, which is not considered a feature of HOS, one had insufficient power to determine statistically significant linkage, and diagnoses in two had the unusual requirement of bilateral limb deformity.…”

Section: (Pediatr Res 58: 981-986 2005)mentioning

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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“…[1][2][3][4][5] The gene for Holt-Oram syndrome has been identified as TBX5 on chromosome 12q24. [6][7][8][9][10][11] TBX5 encodes a protein of 518 amino acids that belongs to the family of the T box transcriptional factors, 10 11 and is expressed in embryonic heart and limb tissues, consistent with its involvement in development of the heart and skeletal structures.…”

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confidence: 99%