Expanding the Phenotype of <scp>TAB2</scp> ‐Related Syndrome: The First Case With Cleft Palate and Insights Into Palatal Development

Over the past decade, heterozygous and disease-causing loss-of-function (LoF) variants in TAB2 gene (also known as TAK1-Binding Protein 2 or MP3K7IP2, OMIM *605101, located on chromosome 6q25.1) have been associated with autosomal dominant “nonsyndromic congenital heart defects, type 2” (OMIM #614980). Presentation of congenital heart defects (CHDs) in affected individuals exhibits significant variability, including dilated cardiomyopathy, hypertrophic cardiomyopathy, mitral valve defects, tricuspid defects, aortic defects, bicuspid aortic valve, aortic coarctation, patent ductus arteriosus, ventricular septal defect, atrial septal defect (ASD) and patent foramen ovale (PFO) (Cheng et al. 2017; Hanson et al. 2022). Cardiac arrhythmias have been reported in some patients (Engwerda et al. 2021). More recently, non-cardiac features have been described defining a more complex syndromic phenotype, including facial dysmorphisms, growth abnormalities, hypotonia, developmental delay, myopia, hearing loss, intellectual disability and connective tissue abnormalities (Caulfield et al. 2018; Woods et al. 2022; Ritelli et al. 2018; Cheng et al. 2017; Engwerda et al. 2021; Westphal et al. 2022). Main facial features are frontal bossing, short and narrow palpebral fissures, dental anomalies, ptosis and hypertelorism (Woods et al. 2022; Cheng et al. 2017; Hanson et al. 2022). Palatal abnormalities, such as high-arched palate, have been reported in four patients in the existing literature (Caulfield et al. 2018; Woods et al. 2022). We report the first documented case of cleft palate in a patient with a TAB2 variant. Based on the observation of our cohort and a review of the literature, we propose that cleft palate and other palatal anomalies should be considered within the phenotypic spectrum of TAB2-related syndrome. We here describe four patients from two different families with TAB2 pathogenic variants who came to the attention of our clinical genetics' unit (refer to Table 1 for the complete description of each patient). The first patient (F1P), an 8-year-old male, presented with a complex clinical picture characterized by severe developmental delay, mitral and tricuspid valve insufficiency, and dysmorphic features. Notably, he also presented with a cleft palate, a finding not previously reported in association with TAB2 in the literature. Exome sequencing identified a de novo truncating variant [NM_001292034.3:c.866dup; p.(Pro290ThrfsTer14)] in the TAB2 gene (see Table 1). This variant is expected to result in a premature stop codon and a non-functional protein, consistent with the LoF mechanism described for other pathogenic TAB2 variants. The remaining three patients in our cohort (F2P, F2M, and F2U) belong to the same family and exhibited a similar phenotype, including multiple CHDs, short stature, and facial dysmorphic features such as hypertelorism, depressed nasal bridge, and anteverted nostrils. High-arched palate was observed in all three patients. The proband (F2P), a 3-year-old male, presented with failure to thrive, tricuspid and mitral valve insufficiency, and PFO. His mother (F2M), a 23-year-old woman, had aortic valve insufficiency, left ventricular dilation, and mild cognitive delay; she also experienced a spontaneous pregnancy loss at 17 weeks due to fetal cardiac malformation and hydrops. Her brother (F2U), the maternal uncle of F2P, presented with left ventricular dilation, tricuspid valve insufficiency, ASD, systolic dysfunction, and mild cognitive delay. A splicing likely pathogenic variant in the TAB2 gene was identified for all of them (c.1604-1G>A). Both the splicing variant c.1604-1G>A and the truncating variant c.866dup; p.(Pro290ThrfsTer14) in the TAB2 gene are novel and have not been previously reported in literature. Hypertelorism Depressed nasal bridge Anteverted nostrils Upslanting palpebral fissure Synophrys Dental overcrowding Hypertelorism Depressed nasal bridge Anteverted nostrils Low set ears Micrognathia Hypertelorism Depressed nasal bridge Anteverted nostrils Low set ears Arched eyebrows Hypertelorism Depressed nasal bridge Anteverted nostrils Mitral insufficiency Tricuspidal insufficiency Tricuspid insufficiency Mitral insufficiency Patent forame ovale Left ventricular dilatation Tricuspid insufficiency Atrial septal defect Systolic dysfunction Left ventricular dilatation Aortic valve insufficiency Global psychomotor delay Behavioral and emotional issues Hearing loss Bone age delay of 3 years on wrist radiograph In our small cohort, all patients presented with palate abnormalities, either a high-arched palate (F2P, F2M and F2U) or a cleft palate (F1P). The clinical findings in our cohort, particularly the novel case of cleft palate, prompted a deeper exploration into the molecular pathways potentially linking TAB2 variants to palatal development. The TAB2 protein has proven in vivo to be a crucial activator of TGF-β activated kinase 1 (TAK1, also named MAP3K7), an essential kinase involved in multiple signaling cascades, most notably the Transforming Growth Factor beta (TGF-β) and Bone Morphogenic Protein 4 (BMP4) pathways as well as in inflammatory signaling pathways mediated by IL-1, TNF and RANKL (Yamaguchi et al. 1995; Shibuya et al. 1998; Liu et al. 2012; Besse et al. 2007; Takaesu et al. 2000). LoF variants in TAK1 have been associated with cardiospondylocarpofacial syndrome (CSCF) (OMIM #157800) and autosomal dominant frontometaphyseal dysplasia (AD-FMD) (OMIM #617137), both of which share striking phenotypic overlap with the TAB2-related syndrome (Wade et al. 2017). The main overlapping features are mild cognitive delay, small stature, failure to thrive, hypertelorism, broad nasal bridge, hearing loss, dental anomalies, septal and valve defects along with joint hypermobility. Other manifestations of AD-FMD include bowed long bones, joint contractures, delayed bone development, muscle weakness, conductive hearing loss and various CHDs. Significantly, palatal anomalies, including cleft palate and bifid uvula have been reported in patients with pathogenic TAK1 variants. Among the 17 patients with pathogenic variants in TAK1 described by Wade et al. (2017), six exhibited either cleft palate or bifid uvula (6/17). Extensive in vivo studies in murine models have provided evidence supporting the direct correlation between Tak1 and cleft palate. We hereby provide a brief overview of the in vivo evidence demonstrating the involvement of Tak1 in palatogenesis. Song et al. (2013) demonstrated that inactivation of Tak1 in mice neural crest cells (CNCs) resulted in failed palate elevation and subsequently complete clefting of the secondary palate. Tak1 −/− mice died perinatally, exhibiting a cleft palate defect with full penetrance, micrognathia, hypoplastic calvarial bones and malformed tongue, resembling human Pierre Robin sequence cleft of the secondary palate (Song et al. 2013). Tak1 deficiency led to Fgf10 overexpression in the developing tongue, determining an enhanced cell proliferation, which determined an upward displacement of the tongue, preventing palate elevation and resulting in cleft palate (Song et al. 2013). Moreover, Tak1 has been implicated in programmed cell death (PCD) and in the Shh pathway, both of which have been correlated to the pathogenesis of cleft palate (Huang et al. 2025; Cuervo et al. 2002; Chen and Huang 1999; Hunter et al. 2019; Xu et al. 2023; Lan and Jiang 2009; Vaivads et al. 2023). To summarize the points discussed so far, Tak1 has been proven in vivo to be fundamental in the pathogenesis of cleft palate, as Tak1 −/− mouse models exhibit cleft palate with full penetrance. Moreover, Tak1 has proven to be strongly associated in vivo with Fgf10 and Shh genes as well as TGF-β, BMP4, and PCD signaling pathways, which have all been implicated in the pathogenesis of cleft palate (Shibuya et al. 1998; Liu et al. 2012; Song et al. 2013; Hunter et al. 2019). Clinical evidence of palatal clefting in patients has been reported in patients with TAK1 pathogenic variants (Wade et al. 2017). Given the strong in vivo interaction between Tak1 and Tab2 along with clinical evidence of palate clefting in our cohort, it is plausible to hypothesize that TAB2 could contribute to this process, likely through the same developmental pathways. TAB2-related syndrome is a rare disorder that is not yet fully characterized, with approximately 80 cases reported in the literature. We add four new cases to the existing TAB2 literature, including two novel variants [c.1604-1G>A and c.866dup; p.(Pro290ThrfsTer14)]. Most significantly, we report the first documented case of a TAB2 patient with cleft palate. We also emphasize that other subtle palatal anomalies, such as high-arched palate, may be an under-recognized feature in this condition. In light of the established in vivo role of TAK1 in cleft palate pathogenesis, the presence of cleft palate in TAK1 patients and the observation of palatal anomalies on our TAB2 cohort, we hypothesize that TAB2 may likewise contribute to palatal development. To date, no study has evaluated the role of TAB2 in palatogenesis and cleft palate pathogenesis so far, unlike TAK1, whose function in these processes has been already well characterized. A.D.R. was the major contributor to the revision of the literature. A.D.R. and S.K. wrote the manuscript. F.S. is the clinician in charge of the clinical genetics department and of the patients described, M.C. is a resident doctor in clinical genetics who followed the patients with him. A.A. and A.C.C. are the cardiologists in charge of the pediatric patients and addressed them to the attention of the clinical geneticist. E.G. and A.C. are the molecular biologist in charge of the NGS analysis and Sanger sequencing performed for the patients described. All authors provided valuable comments, read and approved the final manuscript. This work was supported by the Italian Ministry of Health Ricerca Corrente 2022–2024 to IRCCS Policlinico San Matteo Foundation and by Genoma mEdiciNa pERsonalizzatA (GENERA, T3-AN-04). This work was supported by Italian Ministry of Health Ricerca Corrente 2022–2024, Genoma mEdiciNa pERsonalizzatA (T3-AN-04). The authors declare no conflicts of interest. The data that support the findings of this study are contained within the article and publicly available articles cited. Further inquiries about the clinical course of the described patients may be directed to the corresponding author upon reasonable request.