Genetic Heterogeneity of Heart-Hand Syndromes

Basson, Craig T.; Solomon, Scott D.; Weissman, Barbara; MacRae, Calum A.; Poznanski, Andrew K.; Prieto, Félix; Fuente, Salvador Ruiz de la; Pease, W E; Levin, S. E.; Holmes, Lewis B.; Seidman, J. G.; Seidman, Christine E.

doi:10.1161/01.cir.91.5.1326

Cited by 67 publications

(46 citation statements)

References 13 publications

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“…hand malformations, cardiac septation defects, and/or atrioventricular conduc- Importantly, a wide variety of heart-hand syndromes have been described (23,24) and although they may be familial as well, it is essential to recognize that they can be distinct from HOS. One subject (#16) with a personal and family history of ulnar ray abnormalities along with cardiac and renal malformations was subsequently shown to have a TBX3 mutation (Fig.…”

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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“…Individuals with evidence of radial ray skeletal abnormalities were considered affected by Holt-Oram syndrome if they or at least one family member also had congenital cardiac defects or conduction disease. Clinical evaluations of families A, B, and F have been reported previously (15,25).…”

Section: Methodsmentioning

confidence: 99%

Different TBX5 interactions in heart and limb defined by Holt–Oram syndrome mutations

Basson

Huang

Lin

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

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To better understand the role of TBX5, a T-box containing transcription factor in forelimb and heart development, we have studied the clinical features of HoltOram syndrome caused by 10 different TBX5 mutations. Defects predicted to create null alleles caused substantial abnormalities both in limb and heart. In contrast, missense mutations produced distinct phenotypes: Gly80Arg caused significant cardiac malformations but only minor skeletal abnormalities; and Arg237Gln and Arg237Trp caused extensive upper limb malformations but less significant cardiac abnormalities. Amino acids altered by missense mutations were located on the three-dimensional structure of a related T-box transcription factor, Xbra, bound to DNA. Residue 80 is highly conserved within T-box sequences that interact with the major groove of target DNA; residue 237 is located in the T-box domain that selectively binds to the minor groove of DNA. These structural data, taken together with the predominant cardiac or skeletal phenotype produced by each missense mutation, suggest that organ-specific gene activation by TBX5 is predicated on biophysical interactions with different target DNA sequences.

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“…5 and GATA-4, of gene expression during embryogenesis, and loss of its activity markedly impairs development of the heart and limb. 81,128,129 Although there is significant genetic heterogeneity to the broader class of heart-hand syndromes, 130 there is little if any genetic heterogeneity among Holt-Oram patients. Mutational analyses of the TBX5 gene-coding regions will detect mutations in approximately three fourths of such patients, and the remainder are likely to have mutations in regulatory regions or to have deletions/insertions not detectable by current mutational analysis.…”

Section: Noonan Syndromementioning

confidence: 99%

Genetic Basis for Congenital Heart Defects: Current Knowledge

Pierpont¹,

Basson²,

Benson³

et al. 2007

Circulation

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750

377

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Abstract-The intent of this review is to provide the clinician with a summary of what is currently known about the contribution of genetics to the origin of congenital heart disease. Techniques are discussed to evaluate children with heart disease for genetic alterations. Many of these techniques are now available on a clinical basis. Information on the genetic and clinical evaluation of children with cardiac disease is presented, and several tables have been constructed to aid the clinician in the assessment of children with different types of heart disease. Genetic algorithms for cardiac defects have been constructed and are available in an appendix. It is anticipated that this summary will update a wide range of medical personnel, including pediatric cardiologists and pediatricians, adult cardiologists, internists, obstetricians, nurses, and thoracic surgeons, about the genetic aspects of congenital heart disease and will encourage an interdisciplinary approach to the child and adult with congenital heart disease. (Circulation. 2007;115:3015-3038.)

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Genetic Heterogeneity of Heart-Hand Syndromes

Abstract: We demonstrate that heart-hand syndromes are genetically heterogeneous. Conditions that clinically appear to be partial phenocopies of Holt-Oram syndrome arise from distinct disease genes.

Cited by 67 publications

References 13 publications

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

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

Different TBX5 interactions in heart and limb defined by Holt–Oram syndrome mutations

Genetic Basis for Congenital Heart Defects: Current Knowledge

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