TBX5 variant with the novel phenotype of mixed‑type total anomalous pulmonary venous return in Holt‑Oram Syndrome and variable intrafamilial heart defects
- Authors:
- Published online on: May 4, 2022 https://doi.org/10.3892/mmr.2022.12726
- Article Number: 210
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Copyright: © Azab et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Congenital heart diseases (CHDs), which may have a significant impact on cardiac structure, function, or both, are the most common defects in liveborn children (1). Affecting the heart and/or great vessels, CHDs can be isolated or identified within a syndromic presentation; they are highly diverse, ranging from asymptomatic to fatal. Multiple genetic factors have been implicated in playing a role in CHDs' complex etiology (2).
Most of the known CHD causative genes encode transcription factors (TF) that assist in regulating the cardiac embryogenesis, such as NKX2-5, GATA5, TBX20, TBX1, GATA4, GATA6, TBX5, MEF2C, HAND1, NR2F2, and HAND2 (3). Among the identified TF genes are the T-box gene family, which encodes proteins notably harboring a well-conserved T-box domain which assists in DNA binding (4). One of the T-box genes is TBX5 (OMIM ID: 601620) that is predominantly expressed in the heart and the forelimbs (5). Pathogenic variants in TBX5 have been associated with Holt-Oram syndrome (HOS; OMIM ID: 142900), which is characterized by congenital anomalies in both the heart and the upper limbs, in line with the TBX5 protein expression (6). Interestingly, variants in TBX5 have also been reported to cause non-syndromic CHD (7,8). Previous observations showed that the malformations of HOS were distinctively heterogenous even among individuals sharing the same genetic variant (9–13). A wide phenotypic spectrum of septal defects, conduction abnormalities, and tetralogy of Fallot has been frequently linked to the bulk of the TBX5-associated heart disorders (14). However, the clinical association between HOS and total anomalous pulmonary venous return (TAPVR) has rarely been described (15).
TAPVR makes up 1–3% of the total CHD cases, with an incidence of around 7 per 100,000 live births (16). TAPVR describes the improper connection of the pulmonary veins to the right atrium or to the systemic venous system rather than the normal connection to the left atrium (17). It can also be anatomically sub-divided based on the level of the venous connection anomaly into 4 subtypes (supracardiac, infracardiac, cardiac, and mixed types) (18). To our knowledge, all the studies that claimed the association between HOS and TAPVR were only based on clinical diagnosis-no genetic testing was performed in the previous literature to confirm that TBX5 was the implicated gene (15,19,20). Furthermore, to date, no case of mixed-type TAPVR has been reported in patients with HOS.
Over the past few years, whole-exome sequencing (WES) has been successfully implemented to uncover the underlying molecular etiology of multiple diseases. including CHD (21,22). Consequently, an accurate diagnosis of certain cases was achieved based on the identified genetic findings, which may inform families and influence patient care (23).
We present a multi-generation family affected by autosomal dominant (AD)-CHD with intrafamilial variability of specific manifestations and severity. Interestingly, the proband had a rare lethal mixed-type TAPVR. Our genetic investigation identified a hereditary disease-causing variant (DCV) in the T-box domain of TBX5. Consequently, the identified genetic findings prompted additional phenotyping which modified the diagnosis from non-syndromic CHD to HOS. Noteworthy, this is the first time TBX5 has been associated with TAPVR, specifically, mixed-type TAPVR, in patients with or without HOS. Also, we aimed to augment the previously reported corpus of genetic knowledge related to null-variants in the T-box domain of TBX5 to underpin the phenotypic intra- and interfamilial variable expressivity. Finally, we intended to illustrate the impact of harboring the variant on the protein's structure and function.
Materials and methods
Ethical compliance
This study was conducted in concordance with the tents of the Declaration of Helsinki and was approved by the Institutional Review Board (IRB) of Jordan University Hospital (protocol code 2018/198, 26 June 2018). Before enrollment, written informed consents were secured from the participating individuals and the legal guardian (for the newborn patient).
Clinical assessment
Cardiac clinical evaluation was initially done using echocardiography (Philips HD 11 XE ultrasound system; Philips Healthcare), while the confirmation of diagnosis and detailed anatomy of the pulmonary venous drainage was achieved using contrast computed tomography (CT) scanning (Somatom Definition VA44, 2012; Siemens AG Healthcare).
Study subjects and sample collection
Blood samples were collected using EDTA tubes from the following individuals: III-1, III-2, and the proband (IV-1) (Fig. 1A). DNA isolation was conducted on the collected samples by using Wizard Genomic DNA Purification Kit (Promega) according to the manufacturer's protocol.
WES and data analysis
WES was performed on samples from parents (III-1, and III-2) and proband (IV-1). De-identified genomic DNA samples were provided to Yale under its IRB-approved protocol with a waiver of consent. Trio-exome sequencing was conducted at the Yale Center for Genomic Analysis (YCGA) through the Pediatric Genomics Discovery Program (PGDP, http://www.yalemedicine.org/departments/pediatric-genomics), a program that is freely available to coordinate sequencing, analysis, and additional testing with pediatric critical care researchers caring for children with diseases of suspected genetic etiology. Capture was performed on IDT xGen capture kit followed by Illumina DNA sequencing (HiSeq 4000) using YCGA whole-exome sequencing (WES) protocol. Paired-end sequence reads (101 bases) were converted to FASTQ format and were aligned to the reference human genome (hg19). Genetic variants were called by GATK (24), and they were annotated by ANNOVAR (25) and a custom pipeline that includes population allele frequencies, OMIM and ClinVar citations, and numerous in silico attributes.
The samples were sequenced to a mean depth of at least 110× independent reads per targeted base, with at least 20× independent reads in 98% of targeted bases, or 50× in 90% of targeted bases (Table SI). We filtered exonic or splice-site rare variants (MAF ≤0.01 from publicly available population databases e.g., 1000 Genomes, NHLBI-EVS, gnomAD, and our institutional database) that exhibited high quality sequence reads. De novo variants that were only present in the parents' samples (≥20% alternate allele ratio in the proband, alternate allele ratio <3% in parents) were called. Homozygous or compound heterozygous variants in the proband, or very rare inherited heterozygous variants from target genes were recorded (Table SII,Table SIII,Table SIV,Table SV). All the recorded variants were then visualized and verified manually by Integrative Genomics Viewer (IGV). The visualization of the conserved amino acids flanking the variants was conducted by the help of UCSC browser, GRCh37/hg19 (https://genome.ucsc.edu).
Protein modeling of TBX5 (mutant and wild type)
A template search with BLAST and HHBlits has been performed against the SWISS-MODEL template library (26,27). A total of 30 templates were found. Models are built based on the target-template alignment using ProMod3 (28). Coordinates that are conserved between the target and the template are copied from the template to the model. Insertions and deletions are remodeled using a fragment library. The sidechains are then rebuilt. Finally, the geometry of the resulting model is regularized by using a force field. In case loop modeling with ProMod3 fails, an alternative model is built with PROMOD-II (29). The global and per-residue model quality has been assessed using tools implemented in SWISSS-MODEL, including QMEAN (Qualitative Model Energy Analysis) score and MolProbity score (30). The former is a composite of 6 energy values within the homology model matrix related to protein nativeness, with score values ≤-4.0 indicating poor quality homology models. The latter, on the other hand, combines several protein parameters, including clash score, Ramachandran Plot criteria (Ramachandran Favored and Ramachandran Outliers) (31).
Results
Initial clinical history
The proband (IV-1; Fig. 1A) was a 12-day-old female infant who presented to the emergency room with cyanosis and respiratory distress. Physical examination showed a cyanotic infant with tachypnea and tachycardia. She had no apparent dysmorphic facial features. Evaluation by chest radiography showed a normal-sized heart with bilateral pulmonary congestion. The echocardiographic evaluation showed mixed-type TAPVR, with obstruction of pulmonary venous drainage. There was a drainage of the pulmonary vein to the posterior aspect of the superior vena cava (SVC), with significant obstruction at its entry. In addition, pulmonary venous flow was also seen draining below the diaphragm to the inferior caval vein. The right ventricle (RV) was dilated and hypertrophic with moderate tricuspid regurgitation. The left atrium (LA) was small with right to left shunt at the atrial septum. Left ventricle appeared adequate in size with normal function. The ventricular septum was intact.
The infant was admitted to the pediatric intensive care unit on supplementary oxygen, and a CT angiogram was done the following day to confirm the complex pulmonary venous anatomy (Fig. 2). CT scan showed that the right pulmonary venous confluence (RPVC) drained to the postero-rightward aspect of the superior caval vein, and the left-sided venous confluence (LPVC) coursed behind the left atrium and descended through the diaphragm and drained to the inferior caval vein via a tortuous route (Fig. 2). The patient was transferred to the cardiac center for urgent surgical repair, but unfortunately, at the age of one month, she died before surgery from respiratory failure.
The proband (IV-1), who is the only child in this family, had a family history of CHD from the maternal lineage as it was revealed that her mother (III-2) had ostium secundum atrial septal defect (ASD) for which she underwent surgical repair during childhood (Fig. 1A). Noteworthy, no clinical examinations were done for the distant family members, and the data of their clinical status were based on the provided history.
Genetic analysis
As a rare cardiac anomaly, the finding of TAPVR triggered a genetic workup to better understand this abnormal clinical presentation on the molecular level. The affected proband (IV-1) along with her parents (III-1 and III-2) (Fig. 1A) underwent WES. The trio-based WES analysis revealed a maternally inherited heterozygous nonsense DCV in the TBX5 gene (Table I and Fig. 1B). This DCV (c.577G>T; p.Gly193*) is located in exon 6 at an evolutionarily highly conserved position (GERP score=5.75). Also, this variant is located within the T-box domain of the TBX5 protein (Fig. 1C).
The characteristics and classification of the identified DCV
This DCV in TBX5 (c.577G>T) introduces a stop codon at residue number 193 (p.Gly193*; Table I) of the resultant protein. This premature termination codon (PTC) can lead to the translation of an aberrant short protein-the last 325 amino acids (35% of the protein length) might be lost. Potential nonsense-mediated mRNA decay (NMD) is also a predicted mechanism as the distance between the mRNA's stop codon and the nearest 3′-end of the exon-exon junction is more than 55 nucleotides long. This DCV is absent from the population database (gnomAD; http://gnomad.broadinstitute.org). It has been previously reported in a Chinese Han family with multiple affected individuals with CHDs (32). ClinVar has no prior entry for this variant. Multiple loss-of-function (LoF) variants in TBX5 have been already reported to be disease-causing. Given together, according to the ACMG guidelines (Richards et al 2015), we classify this DCV as pathogenic (Table I) (33). This is the first finding for TBX5 to be associated with the complex cardiac manifestation of mixed-type TAPVR.
Protein modeling of the wild type and mutant (p.Gly193*) versions of TBX5
The resulting homology structure was evaluated employing structure assessment tools within SWISS-MODEL. The results are as follows (in brackets): QMEAN (−0.30), MolProbity score (1.5), Clash score (1.17), Ramachandran Favored (96.42%). The truncated protein was prepared using Discovery Studio (version 4.5). Both wild type (WT) and mutated proteins (in dimer forms) were minimized for 10 steps using Discovery Studio (version 4.5), and then the non-bond interactions between the two units were identified using the implemented tool in Discovery Studio (version 4.5). Fig. 3 shows the significant reduction in the number of non-covalent bond interactions, which clarifies the less stabile state of the mutated dimer form. A significant reduction in the number of non-covalent bonds (interactions) may affect the stability of the dimer formation and thus its binding to DNA.
Outcome of identifying the DCV
Our genetic analysis and interpretation revealed TBX5 as the underlying genetic etiology of the proband's disease. This finding granted re-evaluating the clinical diagnosis of the proband's non-syndromic cardiac anomaly to be part of a manifestation of HOS. A thorough assessment of the family's medical history revealed that the mother (III-2; Fig. 1), carrying the same variant, does indeed have a triphalangeal thumb in her left hand (Fig. 4). In addition, the mother declared the same bilateral thumb anomaly in her deceased child (IV-1).
The finding of triphalangeal thumb in the proband (IV-1) and her affected mother (III-2), along with their respective CHDs, suggested manifestations of HOS in the setting of a DCV in TBX5. This is the first documented HOS patient with the cardiac anomaly of mixed-type TAPVR (Fig. 2).
Discussion
The TBX5 gene encodes for a transcriptional factor protein belonging to the T-box protein family and plays a major role in regulating the early cardiac and upper limb developmental processes (34). Interestingly, TBX5 interacts with other ‘cardiac-critical’ transcriptional factors, such as NKX2-5 and GATA4, which both also help in the early stages of the heart development pathways (35). Thus, genetic variations in the TBX5 can lead to both cardiac and/or skeletal defects (36). Variants in TBX5 cause HOS, also known as the heart-hand syndrome, which is inherited as an AD trait (6).
In this study, we identified the underlying genetic etiology behind a family with AD-CHDs in which the index case presented with mixed-type TAPVR while her mother had ASD. After conducting a trio-based WES analysis, we identified a maternally inherited pathogenic DCV in TBX5. Notably, prior to our investigation, the proband's mother (III-2), who suffered from ASD along with triphalangeal thumb, had never been diagnosed with HOS. The genetic finding of the DCV in TBX5 triggered us to perform a thorough review of her medical records and consequently reached her proper diagnosis with HOS.
LoF variants in TBX5, such as the pathogenic nonsense variant (c.577G>T; p.Gly193*) identified here, are established to be disease-causing in HOS. The resultant protein is predicted to harbor a PTC and probably would yield an aberrantly truncated protein (only 193 out of 518 TBX5′s amino acid residues might be translated, representing nearly 35% of the total protein's length). The transcribed TBX5 mRNA harboring the PTC might instead undergo degradation through the NMD process, resulting in TBX5 haploinsufficiency (37). Previous functional in vitro analysis for this DCV showed that the mutated TBX5 protein failed to activate its targeted genes (MYH6, and NPPA), and no synergistic transactivation between the mutated protein and other transcription factors (NKX2-5, and GATA4) was detected. The designated pathways, which are considered essential for cardiac development, could be nullified in embryos harboring this DCV and probably lead to the consequent heart defect (32). By utilizing protein modeling tools, we studied the impact of harboring this variant (p.Gly193*) on the TBX5′s structure and function. The resultant TBX5 structure formed a destabilized dimer due to a significant reduction in the number of the non-covalent bonds, and its ability to bind DNA might be subsequently deteriorated.
Our findings illustrate that at the intrafamilial level, the elucidated CHD ranged from a simple cardiac manifestation (ASD) to a complex, ultimately lethal one (mixed-type TAPVR). Furthermore, the same DCV (c.577G>T; p.Gly193*) has been previously reported in a Chinese Han family variably affected by ASD and/or ventricular septal defect (VSD), bicuspid aortic valve (BA), and atrial fibrillation (AF) (32). Hence, variable expressivity of the cardiac defects accompanied by this specific DCV can be observed at both the intrafamilial and interfamilial levels, and it is widely ranging in severity, structural deficits, and functional compromise.
The nonsense DCV (c.577G>T; p.Gly193*) is located in the TBX5′s T-box domain. Although pathogenic DCVs have been identified throughout the entire gene, they appear to cluster within this domain in particular (4). The T-box domain is a highly conserved domain across various species; it is also essential for interactions with other transcription factors and DNA binding (38). Therefore, we reviewed the reported clinical effects of the T-box's null variants on the expressivity of cardiac and skeletal malformations (Table II). We noticed that the cardiac defects were mainly associated with limb defects (and thus HOS) and ranged from isolated cases of septal defects (most common) to complex cases presenting with a combination of multiple cardiac manifestations, left ventricular noncompaction cardiomyopathy, conductive heart failure, and even valve anomalies. Nevertheless, this is the first time TBX5 has been discovered to cause mixed-type TAPVR.
Table II.A summary of the T-box's null-variants that are reported in the HGMD Pro (Version 2020.4) database and their associated cardiac manifestations. |
The associated skeletal deformities accompanied by the CHDs in HOS were mainly described in the hand and predominantly in the preaxial radial ray (Table II). Similarly, both the deceased proband (IV-1) and her mother (III-2) presented with a triphalangeal thumb, which has been frequently reported in the literature as a manifestation of HOS (Table II). Other skeletal malformations were reported to a lesser extent in the postaxial region and the other upper extremities (forearms, arms, and shoulder complex), but were rarely ascribed to the lower extremities (feet, hip, etc.), as shown in Table II.
While HOS typically features both cardiac and limb deformities, in certain instances, the severity of the accompanying malformations tends to be more pronounced either in the heart or in the limbs of the same patient. Moreover, a wide range of accompanying anomalies (whether they were cardiac or skeletal) seem to be variably expressed even among patients harboring the same DCV (Table II). Several models propose that the disease-causing mechanism and the severity levels can be attributed to disturbances in TBX5′s binding to downstream protein-partners or recognizing targeted motifs that are vital to the embryo's heart and/or skeletal development, such as NKX2-5, GATA4, GATA6, TBX20, and MEF2C (38).
Although Table II shows a spectrum of the composite cardiac defects, we did not notice any correlation between the type or the location of the null-variant within the T-box domain and the consequent phenotypic severity. Broadly speaking, early studies suggested that type (missense vs. null variants) and/or the location of the DCVs could influence the severity of HOS's cardiac and skeletal manifestations (39). Nonetheless, these observations were based on a small number of cases, and inconsistencies were observed in the later-described ones (36,40). A recent study by Vanlerberghe et al, conducted a phenotype-genotype correlation on the largest molecular investigation of 78 HOS cases and found out that the null-variants were associated with less-severe cardiac manifestations when compared with the missense variants (9). Additionally, no relation was established between the type of the molecular variation (null-variants vs. missense) and the severity of the skeletal anomalies (9). Ultimately, as demonstrated in the family we report, variability is such to prevent predictions of phenotypic consequences based on genotype (40).
The TAPVR subtype identified here revealed both supracardiac and infracardiac venous anomalies, resulting in a mixed-typed classification of the TAPVR phenotype. The 3D CT scan of the proband's heart (IV-) showed that both the RPVC and LPVC failed to connect to the left atrium and instead drained directly into the SVC and IVC, respectively. The mixed-type TAPVR is rare amongst TAPVR cases-accounting for around 5% of the total occurrences (41). Cardiac, supracardiac, and infracardiac subtypes of TAPVR have been previously reported with HOS (15,19,20,42). To the best of our knowledge, mixed-type TAPVR has never been reported in HOS. Hence, this is the first genetic investigation to identify an HOS case with mixed-type TAPVR.
In summary, we utilized the trio-based WES approach to identify a pathogenic nonsense DCV in a family with hereditary CHDs. Also, we showed the importance of genetic testing in reaching the proper diagnosis-our findings aided the correct diagnosis of the proband's and her mother's cases with HOS. We explored the broad phenotypic spectrum of the reported null-variants within the T-box domain of TBX5. Importantly, we reported a patient presenting with mixed-type TAPVR; to our knowledge, this is the first study documenting the connection between the mixed-type TAPVR and HOS. Additionally, this is the first molecular investigation to ever associate TAPVR with HOS.
Supplementary Material
Supporting Data
Acknowledgements
We thank Ms Monica Konstantino (Pediatric Genomics Discovery Program, Yale University Department of Pediatrics, New Haven, USA) for her work in coordinating the samples logistics.
Funding
This work was supported by the Deanship of Academic Research at the University of Jordan (grant no. 2205).
Availability of data and materials
The proband's high-throughput data generated or analyzed during this study are available in the NCBI SRA repository (accession number: PRJNA822821; http://www.ncbi.nlm.nih.gov/biosample/27279246).
Authors' contributions
BA, IAA and SL conceptualized the study. DA interpreted the data. WJ, LJ, NJI, ASAA, HM, YAO, MAS, ZD and MMH performed the data analysis. BA and IAA acquired funding. DA, WJ, NJI, ASAA, HM, YAO, MAS, ZD and MMH designed the methodology. BA, IAA and SL were project administrators and supervised the study. BA, WJ, LJ, NJI, ASAA, HM, YAO, MAS, ZD, IAA and SL conducted the experiments and generated data. DA prepared the figures and tables. BA and DA wrote the original draft. BA, WJ, LJ, IAA and SL wrote, reviewed and edited the manuscript. BA and DA confirm the authenticity of all the raw data. All authors have read and approved the final manuscript.
Ethics approval and consent to participate
This study was conducted in concordance with the tents of the Declaration of Helsinki and was approved by the Institutional Review Board of Jordan University Hospital (approval no. 2018/198; 26 June 2018). Before enrollment, written informed consents were secured from the participating individuals and the legal guardian (for the newborn patient).
Patient consent for publication
The proband's parents provided their consent for the publication of data.
Competing interests
The authors declare that they have no competing interests.
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