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Background: Holt–Oram syndrome is characterised by CHD and limb anomalies. Mutations in TBX5 gene, encoding the T-box transcription factor, are responsible for the development of Holt–Oram syndrome, but such mutations are variably detected in 30–75% of patients. Methods: Clinically diagnosed eight Holt–Oram syndrome patients from six families were evaluated the clinical characteristics, focusing on the cardiac manifestations, in particular, and molecular aetiologies. In addition to the investigation of the mutation of TBX5, SALL4, NKX2.5, and GATA4 genes, which are known to regulate cardiac development by physically and functionally interacting with TBX5, were also analyzed. Multiple ligation-dependent probe amplification analysis was performed to detect exonic deletion and duplication mutations in these genes. Results: All included patients showed cardiac septal defects and upper-limb anomalies. Of the eight patients, seven underwent cardiac surgery, and four suffered from conduction abnormalities such as severe sinus bradycardia and complete atrioventricular block. Although our patients showed typical clinical findings of Holt–Oram syndrome, only three distinct TBX5 mutations were detected in three families: one nonsense, one splicing, and one missense mutation. No new mutations were identified by testing SALL4, NKX2.5, and GATA4 genes. Conclusions: All Holt–Oram syndrome patients in this study showed cardiac septal anomalies. Half of them showed TBX5 gene mutations. To understand the genetic causes for inherited CHD such as Holt–Oram syndrome is helpful to take care of the patients and their families. Further efforts with large-scale genomic research are required to identify genes responsible for cardiac manifestations or genotype–phenotype relation in Holt–Oram syndrome.

Mutations in the gene TBX5 cause Holt‐Oram syndrome (HOS), an autosomal dominant disorder characterized by anterior (i.e., radial ray) upper limb malformations and congenital heart defects and/or cardiac conduction anomalies. The detection rate for TBX5 mutations in HOS patients has been given as 30–35% in most reports. However, a detection rate of 74% was reported when strict clinical inclusion criteria for HOS were applied prior to TBX5 analysis. Still, in a significant proportion of typical HOS cases no mutation can be found within the TBX5 coding region and flanking intronic sequences. One explanation could be that large but submicroscopic deletions of TBX5 could cause HOS, yet only one such TBX5 deletion has been reported to date. We developed a quantitative Real Time PCR strategy to detect large, submicroscopic deletions in TBX5. Using this assay, we screened a total of 102 TBX5 mutation negative patients and discovered two novel intragenic deletions. One deletion of 7756 bp removes exon 6 and a considerable part of the neighboring intronic sequences, and the other of 3695 bp removes exon 9 with the stop codon and the 3′UTR completely as well as a part of the preceding intron 8. We conclude that quantitative Real Time PCR is a reliable method to detect submicroscopic deletions within TBX5. However, such deletions explain only ∼2% of the TBX5 mutational spectrum in HOS cases. In addition, we also present eight novel TBX5 mutations (three nonsense, one splice mutation, four short deletions) as detected by direct sequencing in 21 families not previously analyzed for mutations. © 2006 Wiley‐Liss, Inc.

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 PubMed‐s; 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). © 2005 Wiley‐Liss, Inc.

Superoxide Dismutase 3 (SOD3) scavenges extracellular superoxide giving a hydrogen peroxide metabolite. Both Reactive Oxygen Species diffuse through aquaporins causing oxidative stress and biomolecular damage. SOD3 is differentially expressed in cancer and this research utilises Gene Expression Omnibus data series GSE2109 with 2,158 cancer samples. Genome-wide expression correlation analysis was conducted with SOD3 as the seed gene. Categorical SOD3 Pearson Correlation gene lists incrementing in correlation strength by 0.01 from ρ≥|0.34| to ρ≥|0.41| were extracted from the data. Positively and negatively SOD3 correlated genes were separated for each list and checked for significance against disease overlapping genes in the ClinVar and Orphanet databases via Enrichr. Disease causal genes were added to the relevant gene list and checked against Gene Ontology, Phenotype Ontology, and Elsevier Pathways via Enrichr before the significant ontologies containing causal and non-overlapping genes were reviewed with a literature search for possible disease and oxidative stress associations. 12 significant individually discriminated disorders were identified: Autosomal Dominant Cutis Laxa (p = 6.05x10 -7 ), Renal Tubular Dysgenesis of Genetic Origin (p = 6.05x10 -7 ), Lethal Arteriopathy Syndrome due to Fibulin-4 Deficiency (p = 6.54x10 -9 ), EMILIN-1-related Connective Tissue Disease (p = 6.54x10 -9 ), Holt-Oram Syndrome (p = 7.72x10 -10 ), Multisystemic Smooth Muscle Dysfunction Syndrome (p = 9.95x10 -15 ), Distal Hereditary Motor Neuropathy type 2 (p = 4.48x10 -7 ), Congenital Glaucoma (p = 5.24x210 -9 ), Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome (p = 3.77x10 -16 ), Classical-like Ehlers-Danlos Syndrome type 1 (p = 3.77x10 -16 ), Retinoblastoma (p = 1.9x10 -8 ), and Lynch Syndrome (p = 5.04x10 -9 ). 35 novel (21 unique) genes across 12 disorders were identified: ADNP , AOC3 , CDC42EP2 , CHTOP , CNN1 , DES , FOXF1 , FXR1 , HLTF , KCNMB1 , MTF2 , MYH11 , PLN , PNPLA2 , REST , SGCA , SORBS1 , SYNPO2 , TAGLN , WAPL , and ZMYM4 . These genes are proffered as potential biomarkers or therapeutic targets for the corresponding rare diseases discussed.

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.

To dissect the TBX5 regulatory circuit, we focused on microRNAs (miRNAs) that collectively contribute to make TBX5 a pivotal cardiac regulator. We profiled miRNAs in hearts isolated from wild-type , CRE, Tbx5 lox/ + and Tbx5 del/ + mice using a Next Generation Sequencing (NGS) approach. TBX5 deficiency in cardiomyocytes increased the expression of the miR-183 cluster family that is controlled by Kruppel-like factor 4, a transcription factor repressed by TBX5. MiR-182-5p, the most highly expressed miRNA of this family, was functionally analyzed in zebrafish. Transient overexpression of miR-182-5p affected heart morphology, calcium handling and the onset of arrhythmias as detected by ECG tracings. Accordingly, several calcium channel proteins identified as putative miR-182-5p targets were downregulated in miR-182-5p overexpressing hearts. In stable zebrafish transgenic lines, we demonstrated that selective miRNA-182-5p upregulation contributes to arrhythmias. Moreover, cardiac-specific down-regulation of miR-182-5p rescued cardiac defects in a zebrafish model of Holt–Oram syndrome. In conclusion, miR-182-5p exerts an evolutionarily conserved role as a TBX5 effector in the onset of cardiac propensity for arrhythmia, and constitutes a relevant target for mediating the relationship between TBX5 , arrhythmia and heart development.

Lady J Ríos-Serna,1 Lorena Díaz-Ordoñez,1 Estephania Candelo,1,2 Harry Pachajoa1,3 1Center for Research on Congenital Anomalies and Rare Diseases (CIACER), Department of Basic Medical Sciences, Universidad Icesi, Cali, Valle del Cauca, Colombia; 2Biomaterial and Tissues Engineering and Genetic of Human Diseases, University College London, London, UK; 3Fundación Valle del Lili, Cali, Valle del Cauca, Colombia Abstract: 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 NM₁81486.2:c.243-1G>C was identified. Keywords: Holt-Oram syndrome, heart-hand syndrome, de novo mutation, TBX5.i>

•This case highlights how a combined clinic and home-based therapy approach can allow for long term management of Holt-Oram syndrome.•Caregiver education and understanding of a home exercise program can improve compliance.•This case demonstrates early and consistent orthosis wear can improve passive range of motion.•Modified constraint induced movement therapy may improve hand and digit function pre and postpollicization.•Comprehensive, long-term assessment may be needed to evaluate improvement following surgical procedures for Holt-Oram syndrome. Holt-Oram syndrome (HOS) is a rare, genetic condition characterized by the combination of congenital heart defect and hypoplasia in one or both upper extremities. Children with HOS commonly present with varied joint and limb involvement including radial longitudinal deficiency impacting hand function. Evidence-based guidelines regarding orthotic wear and therapeutic techniques are lacking. The aim of this case report was to present the results of a long-term occupational therapy program for a patient with HOS pre and postpollicization. Case report. A 4-month-old patient with bilateral radial longitudinal deficiencies began outpatient occupational therapy for custom orthosis fabrication and treatment which included long term clinic and home-based intervention. Techniques included passive range of motion, orthosis wear, therapeutic taping, and modified constraint induced movement therapy. Longitudinal assessment of musculoskeletal alignment and functional hand use was performed using goniometry for passive and active range of motion, the Assisting Hand Assessment (AHA), and The Thumb Grasp and Pinch Assessment (T-GAP). Improvement in passive and active range of motion was achieved as well as improved activity level function as measured by the AHA and T-GAP postpollicization and intervention. A combined clinic and home-based therapeutic approach can be effective for children with HOS to improve alignment and function pre and postpollicization to further enhance hand function. Comprehensive, long-term assessment is necessary to fully evaluate and communicate improvement.

Background Ventricular septal defect is the most prevalent form of congenital heart disease, occurring as isolated lesion in approximately 20% of cases and as part of more complex malformations in up to 40%. Multiple ventricular septal defects are usually associated with “Swiss Cheese” variant characterized by multiple perforations throughout the muscular septum, often involving the apical, mid-muscular, and anterior regions, which creates a complex network of left-to-right shunts that are technically difficult to identify and close individually. Presence of severe tricuspid regurgitation contributes to risks related to poor prognosis. An infant with congestive heart failure, severe tricuspid regurgitation, large left-to-right shunting and elevated right ventricular pressure requires a critical decision-making process for surgical management due to higher risks and poor outcome. Case presentation We are presenting herewith a six-month-old infant with Holt-Oram syndrome, who presented with classic signs of congestive heart failure, tachypnoea, poor weight gain and hepatomegaly, all indicative of systemic and pulmonary venous congestion. Chest x-ray and echocardiography confirmed the diagnosis. Despite aggressive medical management the patient’s condition continued to deteriorate and required surgical intervention. The traditional management paradigm for such infants involves a choice between palliative pulmonary artery banding or surgical closure. In this case, both options presented significant risks and were deemed suboptimal. Therefore, to avoid risks, we opted a minimal invasive perventricular device closure of the defects with success. Conclusions Children with severe tricuspid regurgitation, right ventricular failure, Swiss cheese morphology, multiple ventricular septal defects, genetic disorders and low weight may be considered for minimal invasive approaches including perventricular device closure of the ventricular septal defects whenever feasible to avoid operative risks and offer better outcomes.