Identification of TBX5 mutations in a series of 94 patients with Tetralogy of Fallot

Abstract

Tetralogy of Fallot (TOF) (OMIM #187500) is the most frequent conotruncal congenital heart defect (CHD) with a range of intra- and extracardiac phenotypes. TBX5 is a transcription factor with well-defined roles in heart and forelimb development, and mutations in TBX5 are associated with Holt-Oram syndrome (HOS) (OMIM#142900). Here we report on the screening of 94 TOF patients for mutations in TBX5, NKX2.5 and GATA4 genes. We identified two heterozygous mutations in TBX5. One mutation was detected in a Moroccan patient with TOF, a large ostium secundum atrial septal defect and complete atrioventricular block, and features of HOS including bilateral triphalangeal thumbs and fifth finger clinodactyly. This patient carried a previously described de novo, stop codon mutation (p.R279X) located in exon 8 causing a premature truncated protein. In a second patient from Italy with TOF, ostium secundum atrial septal defect and progressive arrhythmic changes on ECG, we identified a maternally inherited novel mutation in exon 9, which caused a substitution of a serine with a leucine at amino acid position 372 (p.S372L, c.1115C>T). The mother's clinical evaluation demonstrated frequent ventricular extrasystoles and an atrial septal aneurysm. Physical examination and radiographs of the hands showed no apparent skeletal defects in either child or mother. Molecular evaluation of the p.S372L mutation demonstrated a gain-of-function phenotype. We also review the literature on the co-occurrence of TOF and HOS, highlighting its relevance. This is the first systematic screening for TBX5 mutations in TOF patients which detected mutations in two of 94 (2.1%) patients.

Genetic profile of isolated congenital diaphragmatic hernia revealed by targeted next‐generation sequencing

“…TBX5 pathogenic variants cause Holt‐Oram syndrome that is characterized by upper limb malformations and cardiac septation defects. Similarly to our patient, skeletal anomalies were absent in a number of families with isolated heart defects supporting a reduced penetrance of this gene for limb anomalies . TBX5 interacts with MEF2C, NKX2‐5, GATA4, and GATA6 to regulate heart development .…”

“…TBX1 : p.(Gly310Ser), TBX5:p.(Ser372Leu), and GATA5 :c.424 T > C, p.(Tyr142His) variants have all been previously reported with congenital heart defects, and their functional characterization supports their pathogenicity . The TBX1 variant has been reported in association with velocardiofacial syndrome in the absence of 22q11 deletion .…”

TBX5 loss-of-function mutation contributes to familial dilated cardiomyopathy

“…Cardiac phenotypes comprise a wide spectrum of congenital heart abnormalities including secundum-type atrial septal defect, ventricular septal defect, atrioventricular septal defect, patent ductus arteriosus, tetralogy of Fallot, mitral valve defect, and aberrant pulmonary vein as well as cardiac conduction block and atrial fibrillation, with atrial septal defect being the most common [20,21,37]. Clinically, there are three variations of Holt-Oram syndrome: patients may have only cardiovascular defects (4%), only forelimb deformities (27%), or both (69%), and these cardiac and skeletal malformations vary widely ranging from mild to severe, even within families [21].…”

TBX20 loss-of-function mutation associated with familial dilated cardiomyopathy

“…Genomic DNA was isolated from whole blood with Wizard Genomic DNA Purification Kit (Promega, Madison, WI, USA). The intronic primers used to amplify the coding exons and flanking introns of TBX20 by polymerase chain reaction (PCR) were designed as previously described [21]. Amplication of TBX20 by PCR was performed using HotStar Taq DNA Polymerase (Qiagen, Hilden, Germany) on a Veriti Thermal Cycler (Applied Biosystems, Foster, CA, USA).…”

“…As a part of a conserved regulatory network, these core cardiac transcription factors physically interact with each other to finely regulate cardiac development and structural remodeling [6][7][8]. Therefore, it is not surprising that an increasing number of mutations in these core cardiac transcription factors, especially for the most extensively investigated NKX2-5, GATA4, GATA5, GATA6, TBX5, and TBX20, have been identified in patients with various CHDs or cardiac arrhythmias [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25]. More interestingly, mutations in some cardiac transcription factors, such as NKX2-5, GATA4, GATA5, GATA6 and TBX5, have also been associated with isolated DCM in humans [26][27][28][29][30][31][32].…”