Novel mutations in the TBX5 gene in patients with Holt-Oram Syndrome

Porto, Marianna Picarelli Ribeiro; Vergani, Naja; Carvalho, Antônio Carlos; Cernach, Mirlene Cecília Soares Pinho; Brunoni, Décio; Perez, Ana Beatriz Alvarez

doi:10.1590/s1415-47572010005000051

Cited by 13 publications

(3 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Other associated anomalies have also been described in HOS patients and may include craniofacial, tracheal, pulmonary, vertebral, renal and lower limb anomalies [ 5 , 32 – 36 ]. These can be incidental findings or may be atypical cases of HOS due to specific sequence variants of the TBX5 gene [ 11 , 36 , 37 ]. We observed single cases with cleft uvula, brain cyst, spleen anomaly, pyelon duplex, ectopic kidney and hemivertrebra.…”

Section: Discussionmentioning

confidence: 99%

Holt Oram syndrome: a registry-based study in Europe

Barišić

Boban

Greenlees

et al. 2014

Orphanet J Rare Dis

View full text Add to dashboard Cite

BackgroundHolt-Oram syndrome (HOS) is an autosomal dominant disorder characterised by upper limb anomalies and congenital heart defects. We present epidemiological and clinical aspects of HOS patients using data from EUROCAT (European Surveillance of Congenital Anomalies) registries.MethodsThe study was based on data collected during 1990–2011 by 34 registries. The registries are population-based and use multiple sources of information to collect data on all types of birth using standardized definitions, methodology and coding. Diagnostic criteria for inclusion in the study were the presence of radial ray abnormalities and congenital heart disease (CHD), or the presence of either radial ray anomaly or CHD, with family history of HOS.ResultsA total of 73 cases of HOS were identified, including 11 (15.1%) TOPFA and 62 (84.9%) LB. Out of 73 HOS cases, 30.8% (20/65) were suspected prenatally, 55.4% (36/65) at birth, 10.7% (7/65) in the first week of life, and 3.1% (2/65) in the first year of life. The prenatal detection rate was 39.2% (20/51), with no significant change over the study period. In 55% (11/20) of prenatally detected cases, parents decided to terminate pregnancy. Thumb anomalies were reported in all cases. Agenesis/hypoplasia of radius was present in 49.2% (30/61), ulnar aplasia/hypoplasia in 24.6% (15/61) and humerus hypoplasia/phocomelia in 42.6% (26/61) of patients. Congenital heart defects (CHD) were recorded in 78.7% (48/61) of patients. Isolated septal defects were present in 54.2 (26/48), while 25% (12/48) of patients had complex/severe CHD. The mean prevalence of HOS diagnosed prenatally or in the early years of life in European registries was 0.7 per 100,000 births or 1:135,615 births.ConclusionsHOS is a rare genetic condition showing regional variation in its prevalence. It is often missed prenatally, in spite of the existence of major structural anomalies. When discovered, parents in 45% (9/20) of cases opt for the continuation of pregnancy. Although a quarter of patients have severe CHD, the overall first week survival is very good, which is important information for counselling purposes.

show abstract

Section: Discussionmentioning

confidence: 99%

Holt Oram syndrome: a registry-based study in Europe

Barišić

Boban

Greenlees

et al. 2014

Orphanet J Rare Dis

View full text Add to dashboard Cite

show abstract

“…Both the radial ray deficiency and the cardiac anomaly were classified into mild or severe according to the criteria shown in Table 1. Table 2 summarizes the clinical features of previously reported cases of missense mutations of the TBX5 gene (Basson et al, 1999;Boogerd et al, 2010;Brassington et al, 2003;Cross et al, 2000;Debeer et al, 2007;Dias et al, 2007;Faria et al, 2008;Furniss et al, 2009;McDermott et al, 2005;Porto et al, 2010;Postma et al, 2008;Yang et al, 2000).…”

Section: Literature Reviewmentioning

confidence: 99%

Molecular basis of the clinical features of Holt–Oram syndrome resulting from missense and extended protein mutations of the TBX5 gene as well as TBX5 intragenic duplications

Al‐Qattan

Al-Shaar

2015

Gene

View full text Add to dashboard Cite

“…Although CHD related mutations are dispersed across all the coding exons of TBX5 gene, the most of them are positioned within the highly evolutionary conserved DNA binding motif (T-box or T-domain), spanning from amino acids 53–241. 10 , 11 Loss-of function mutations in T-box region on the human chromosome 12 (12q24.1) and haploinsufficiency of TBX5 are the cause of CHD. Such nucleotide alterations in T-box affect interactions with the major and minor groove of the target DNA and produce very important heart defects in the developmental pathways of cardiac morphogenesis.…”

Section: Introductionmentioning

confidence: 99%

Identification of a novel non-sense mutation in TBX5 gene in pediatric patients with congenital heart defects

Khatami

Kazeminasab

et al. 2018

J Cardiovasc Thorac Res

View full text Add to dashboard Cite

Introduction: Congenital heart diseases (CHDs) are structural cardiovascular malformations that arise from abnormal development of the heart during the prenatal life. Mutations in the TBX5 gene, encoding T-box transcription factor, are a major cause of CHD. To evaluate the TBX5 mutations in hotspot exons in sporadic pediatric patients with CHD phenotypes, analytical case/control study performed in an Iranian cohort of unrelated patients with clinical diagnosis of congenital heart malformations. Methods: We investigated TBX5 coding exons 4, 5, 6 and 7 in 95 sporadic patients with CHD phenotypes and compared to 82 healthy controls using PCR-SSCP and DNA sequencing approaches. Results: We report here on a novel and heterozygote Non-sense mutation in exon 5 of TBX5, E128X (G14742T), in two Iranian children. This mutation locates inside the T-box and both of pediatric patients carrying this novel mutation suffer from severe heart malformations. The G14742T mutation leads to the substitution of glutamic acid (E) by stop codon (X) at residue 128, an evolutionarily conserved position in T-box as well as in other species. The non-sense mutation of E128X was predicted to be pathogenic by Mutation Taster and Polyphen software programs. Conclusion: TBX5 E128X mutation results in a translational premature stop. This type of mutation results in a shortened protein that may function improperly and which cannot bind to other transcription factors; therefore, haploinsufficiency of TBX5 protein is presumably causing the severe cardiac malformations in these patients.

show abstract

Novel mutations in the TBX5 gene in patients with Holt-Oram Syndrome

Cited by 13 publications

References 26 publications

Holt Oram syndrome: a registry-based study in Europe

Holt Oram syndrome: a registry-based study in Europe

Molecular basis of the clinical features of Holt–Oram syndrome resulting from missense and extended protein mutations of the TBX5 gene as well as TBX5 intragenic duplications

Identification of a novel non-sense mutation in TBX5 gene in pediatric patients with congenital heart defects

Contact Info

Product

Resources

About