Familial Heart Disease With Skeletal Malformations

Holt, Mary; Oram, Samuel

doi:10.1136/hrt.22.2.236

Cited by 457 publications

(227 citation statements)

References 6 publications

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“…It was first described as a syndrome of upper limb abnormalities and congenital heart defects by Holt and Oram. 1 It is inherited in an autosomal dominant manner with high penetrance and variable expression (ranging from only subclinical skeletal findings to phocomelia, and from conduction defects to severe congenital heart defects). The typical combination is thought to be triphalangeal thumbs and a secundum atrial septal defect (ASD), but there is a range in severity of limb and heart defects.…”

Section: Introductionmentioning

confidence: 99%

“…This results in features ranging from limitation in movement, triphalangeal or absent thumbs, foreshortened forearms, to phocomelia. 1,4 The thumbs are the most commonly affected structure (84%), with radial aplasia/hypoplasia in 64%. Ulnar ray defects have been shown to occur only when the radial ray is involved, and to a lesser degree of severity.…”

Section: Introductionmentioning

confidence: 99%

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TBX5 intragenic duplication: a family with an atypical Holt–Oram syndrome phenotype

Patel

Silcock²,

McMullan³

et al. 2012

Eur J Hum Genet

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Holt-Oram syndrome (HOS) is a rare autosomal dominant heart-hand syndrome due to mutations in the TBX5 transcription factor. Affected individuals can have structural cardiac defects and/or conduction abnormalities, and exclusively upper limb defects (typically bilateral, asymmetrical radial ray defects). TBX5 mutations reported include nonsense, missense, splicing mutations and exon deletions. Most result in a null allele and haploinsufficiency, but some impair nuclear localisation of TBX5 protein or disrupt its interaction with co-factors and downstream targets. We present a five generation family of nine affected individuals with an atypical HOS phenotype, consisting of ulnar ray defects (ulnar hypoplasia, short fifth fingers with clinodactyly) and very mild radial ray defects (short thumbs, bowing of the radius and dislocation of the radial head). The cardiac defects seen are those more rarely reported in HOS (atrioventricular septal defect, hypoplastic left heart syndrome, mitral valve disease and pulmonary stenosis). Conduction abnormalities include atrial fibrillation, atrial flutter and sick sinus syndrome. TBX5 mutation screening (exons 3-10) identified no mutations. Array comparative genomic hybridisation (CGH) revealed a 48 kb duplication at 12q24.21, encompassing exons 2-9 of the TBX5 gene, with breakpoints within introns 1-2 and 9-10. The duplication segregates with the phenotype in the family, and is likely to be pathogenic. This is the first known report of an intragenic duplication of TBX5 and its clinical effects; an atypical HOS phenotype. Further functional studies are needed to establish the effects of the duplication and pathogenic mechanism. All typical/atypical HOS cases should be screened for TBX5 exon duplications.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

TBX5 intragenic duplication: a family with an atypical Holt–Oram syndrome phenotype

Patel

Silcock²,

McMullan³

et al. 2012

Eur J Hum Genet

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“…The typical features of the syndrome were first described by Oram in 1960 (Holt andOram, 1960). The disorder, which has an estimated frequency of 1 in 100,000 live births, shows complete penetrance and high intra-and interfamilial variability of clinical expression (Newbury-Ecob et al, 1996).…”

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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“…Наиболее распространенными и клиниче-ски значимыми синдромами, в состав которых входит врожденная лучевая косорукость, явля-ются: тромбоцитопения с отсутствием лучевых костей (TAR-синдром), синдром Холта -Орама (синдром «рука -сердце»), VACTERL-синдром (VATER-ассоциация, VATER-синдром), синдром Нагера (акрофациальный дизостоз) [1][2][3][9][10][11][12]. Менее распространенными являются синдром Баллера -Герольда, синдром Миллера, синдром Робертса [5,13].…”

Section: Introductionunclassified

“…Описываемая частота встречаемости -1 на 100 000 живорожденных младенцев. Генетические исследования показали наличие мутации в гене ТВХ5 [10]; тип наследования -аутосомно-доми-нантный (60 %) или спорадический (40 %) [12].…”

Section: Introductionunclassified