A novel missense mutation in the TBX5 gene in a Saudi infant with Holt-Oram syndrome.
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ABSTRACT:
SUBMITTER: Al-Qattan MM
PROVIDER: S-EPMC4549596 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Holt-Oram syndrome (HOS) is an autosomal dominant disorder characterized by congenital cardiac defects and congenital deformities of the upper limbs. Herein, we report the case of a 2-year-old patient presenting with clinical diagnostic criteria of HOS with interatrial and interventricular communication associated with hip dysplasia and upper limb reduction composed of radial ray anomaly. A novel de novo, potentially pathogenic variant in the TBX5 gene at NM_181486.2:c.243-1G>C was identified.
| S-EPMC6260184 | biostudies-literature
Project description: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 upper-limb malformations (7). Pathogenic mutations in the TBX5 gene were found in four HOS patients, including two new mutations (c.374delG; c.678G > T) in typical patients, and the hotspot mutation c.835C > T in two patients, one of them with an atypical HOS phenotype involving lower-limb malformations. Two new mutations in the GATA4 gene were found in association with isolated upper-limb malformations, but their clinical significance remains to be established. A previously described possibly pathogenic mutation in the NKX2.5 gene (c.73C > 7) was detected in a patient with isolated heart malformations and also in his clinically normal father.
| S-EPMC3036863 | biostudies-literature
Project description:Holt-Oram syndrome (HOS) is an autosomal dominant developmental defect involving preaxial radial ray upper limb deformity and variable cardiac defects. It has been demonstrated that HOS is caused by mutations in the T-box transcription factor gene TBX5. Numerous germline mutations (more than 60) of this gene produce preterminal stop codons, which lead to synthesis of a truncated nonfunctional TBX5 protein. The haplo-insufficiency of the TBX5 gene is the most significant cause of HOS. We report on a sporadic patient with clinical features of HOS. Our patient had a cardiac anomaly - a muscular ventricular and atrial septal defect, patent ductus arteriosus and a conduction defect (a first-step atrioventricular block). Upper limb anomalies in our patient were relatively mild and unusual to HOS - distally displaced thumbs, narrow shoulders and hypotrophy of the muscles in the shoulder region. Molecular analysis identified a novel and unusual heterozygous frameshift mutation - c.1304delT (p.Leu435fsX146) - in exon 9 of the TBX5 gene, which is predicted to cause an elongated TBX5 protein with 84 miscoding amino acids and 62 supernumerary C-terminal amino acids. To the best of our knowledge, only one such type of elongation mutation has thus far been reported in the TBX5 gene.
| S-EPMC3214961 | biostudies-literature
Project description:Introduction: Holt-Oram syndrome (HOS) is a rare genetic disorder characterized by upper limb abnormalities, congenital heart defects, and/or conduction abnormalities. Sequence alteration of T-box transcription factor 5 (TBX5) is correlated with the incidence of HOS. Case description: We present the case of a 24-year-old female with upper limb alterations (congenital dysplasia in the wrist and elbow joints) and an anomalous left main trunk arising from the right coronary sinus. The patient inherited a base T (reference C) at rs883079 from her mother and base C (reference T) at rs10850326 from her father, both of which belong to the 3'-untranslated region (UTR) of the TBX5 gene; no alterations in TBX5 expression or single-nucleotide polymorphisms (SNPs) in other exon areas were found. We explored the effects of TBX5 on cardiomyocytes using the HL-1 cell line and TBX5-knockdown cells. Discussion: Quantitative polymerase chain reaction analysis demonstrated that TEKT2, TEKT4, and SPTB expression decreased after TBX5 knockdown, while chromatin immunoprecipitation analysis further revealed that TBX5 binds to the TEKT2, TEKT4, and SPTB promoter regions to promote gene transcription. Our findings support a novel TBX5-related pathogenic mechanism in HOS.
| S-EPMC10014717 | biostudies-literature
Project description:Mutations in TBX5, a T-box-containing transcription factor, cause cardiac and limb malformations in individuals with Holt-Oram syndrome (HOS). Mutations that result in haploinsufficiency of TBX5 are purported to cause cardiac and limb defects of similar severity, whereas missense mutations, depending on their location in the T box, are thought to cause either more severe heart or more severe limb abnormalities. These inferences are, however, based on the analysis of a relatively small number of independent cases of HOS. To better understand the relationship between mutations in TBX5 and the variable expressivity of HOS, we screened the coding and noncoding regions of TBX5 and SALL4 for mutations in 55 probands with HOS. Seventeen mutations, including six missense mutations in TBX5 and two mutations in SALL4, were found in 19 kindreds with HOS. Fewer than 50% of individuals with nonsense or frameshift mutations in TBX5 had heart and limb defects of similar severity, and only 2 of 20 individuals had heart or limb malformations of the severity predicted by the location of their mutations in the T box. These results suggest that neither the type of mutation in TBX5 nor the location of a mutation in the T box is predictive of the expressivity of malformations in individuals with HOS.
| S-EPMC1180592 | biostudies-literature
Project description: Not available
| S-EPMC1768780 | biostudies-literature
Project description:BackgroundThe Holt-Oram syndrome (HOS) is an autosomal dominant disorder affecting 1/100.000 live births. It is defined by upper limb anomalies and congenital heart defects with variable severity. We describe a dramatic phenotype of a male, 15-month-old patient being investigated for strict diagnostic criteria of HOS.Methods and resultsGenetic analysis revealed a so far unpublished TBX5 mutation, which occurs de novo in the patient with healthy parents. TBX5 belongs to the large family of T-box transcription factors playing major roles in morphogenesis and cell-type specification. The mutation located in the DNA-binding domain at position 920 (C→A) leads to an amino acid change at position 85 (proline → threonine). Three-dimensional analysis of the protein structure predicted a cis to trans change in the respective peptide bond, thereby probably provoking major conformational and functional alterations of the protein. The p.Pro85Thr mutation showed a dramatically reduced activation (97%) of the NPPA promoter in luciferase assays and failed to induce NPPA expression in HEK 293 cells compared to wild-type TBX5 protein. The mutation did not interfere with the nuclear localization of the protein.ConclusionThese results suggest that the dramatic functional alteration of the p.Pro85Thr mutation leads to the distinctive phenotype of the patient.
| S-EPMC5023941 | biostudies-literature
Project description: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.
| S-EPMC3400730 | biostudies-literature
Project description: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 Holt-Oram 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.
| S-EPMC15870 | biostudies-literature
Project description:Holt-Oram syndrome (HOS) is an autosomal dominant condition characterised by the association of congenital heart defect (CHD), with or without rhythm disturbances and radial defects, due to TBX5 variants. The diagnosis is challenged by the variability of expression and the large phenotypic overlap with other conditions, like Okihiro syndrome, TAR syndrome or Fanconi disease. We retrospectively reviewed 212 patients referred for suspicion of HOS between 2002 and 2014, who underwent TBX5 screening. A TBX5 variant has been identified in 78 patients, representing the largest molecular series ever described. In the cohort, 61 met the previously described diagnostic criteria and 17 have been considered with an uncertain HOS diagnosis. A CHD was present in 91% of the patients with a TBX5 variant, atrial septal defects being the most common (61.5%). The genotype-phenotype study highlights the importance of some critical features in HOS: the septal characteristic of the CHD, the bilateral and asymmetric characteristics of the radial defect and the presence of shoulder or elbow mobility defect. Besides, 21 patients presented with an overlapping condition. Among them, 13 had a typical HOS presentation. We discuss the strategies that could be adopted to improve the molecular delineation of the remaining typical patients.
| S-EPMC6460573 | biostudies-literature