Abstract:The Holt-Oram syndrome (HOS) is an autosomal dominant condition characterized by upper limb and cardiac malformations. Mutations in the TBX5 gene cause HOS and have also been associated with isolated heart and arm defects. Interactions between the TBX5, GATA4 and NKX2.5 proteins have been reported in humans. We screened the TBX5, GATA4, and NKX2.5 genes for mutations, by direct sequencing, in 32 unrelated patients presenting classical (8) or atypical HOS (1), isolated congenital heart defects (16) or isolated … Show more
“…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.…”
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.
“…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.…”
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.
“…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).…”
“…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.…”
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.
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