Case report: A novel de novo loss of function variant in the DNA-binding domain of TBX2 causes severe osteochondrodysplasia

Rafeeq, Misbahuddin M; Murad, Hussam; Najumuddin,; Ullah, Sana; Ahmed, Zaheer; Alam, Qamre; Bilal, Muhammad; Habib, Alaa Hamed; Sain, Ziaullah M; Khan, Muhammad Jawad; Umair, Muhammad

doi:10.3389/fgene.2022.1117500

Cited by 2 publications

(3 citation statements)

References 25 publications

(37 reference statements)

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“…The TBX2 gene encodes a transcription factor that belongs to the family of T-box factor proteins that bind to DNA. Several missense and stop-gain variants of TBX2 have been associated with conotruncal heart defects, vertebral anomalies, variable endocrine, and osteochondrodysplasia (25)(26)(27).…”

Section: Discussionmentioning

confidence: 99%

“…Several large deletions encompassing TBX2 have been reported associated with human developmental disorders, skeletal malformations, and cardiac defects (21)(22)(23). Although TBX2 variants are linked to various disorders, such as conotruncal heart defects (MIM:217095) (24), vertebral anomalies and variable endocrine and T-cell dysfunction (MIM:618223) (25), as well as osteochondrodysplasia (26,27), the association between TBX2 dysfunction and human hearing loss remains unproven, rendering the role of TBX2 in the human cochlea uncertain.…”

Section: The Auditory Epithelium Comprises Two Types Of Sound Recepto...mentioning

confidence: 99%

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Frameshift variants inTBX2underlie autosomal-dominant hearing loss with incomplete penetrance of nystagmus

Hua,

Wang,

et al. 2024

Preprint

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Purpose: The transcription factor TBX2 plays a critical role in inner hair cells development in mice. Yet, the link between TBX2 malfunction and human hearing-related disorders remains unexplored. Methods: Linkage analysis combined with whole genome sequencing was applied to identify the causative gene in two autosomal dominant Chinese families characterized by late-onset progressive sensorineural hearing loss and incomplete penetrance of horizontal oscillatory nystagmus. Functional evaluation of TBX2 variants was performed through protein expression, localization, and transcriptional activity analysis in vitro, phenotypic analysis and mechanism study in knockout mice model in vivo. Results: Multipoint parametric linkage analysis of Family 1 revealed a maximum LOD score of 3.01 on chromosome 17q23.2. Whole genome sequencing identified distinct TBX2 variants, c.977delA (p.Asp326Alafs*42) and c.987delC (p.Ala330Argfs*38) in each family, co-segregating with hearing loss. These variants resulted in premature termination and the generation of a new peptide segment, reducing transcriptional activity. Further, heterozygous Tbx2 knockout mice exhibited late-onset progressive hearing loss, along with ectopic expression of Prestin in IHCs and a gradual decrease in expression from P7 to P42. Conclusion: Our findings indicate that heterozygous TBX2 frameshift variants are the genetic cause of late-onset progressive hearing loss and incomplete penetrance of nystagmus. The heterozygous Tbx2 knockout mouse model mirrored the human hearing loss phenotype, further validating TBX2's role in auditory function. These insights enhance our understanding of TBX2 in the auditory system, providing valuable information for molecular diagnostics and genetic counseling in related hearing disorders.

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Section: Discussionmentioning

confidence: 99%

Section: The Auditory Epithelium Comprises Two Types Of Sound Recepto...mentioning

confidence: 99%

Frameshift variants inTBX2underlie autosomal-dominant hearing loss with incomplete penetrance of nystagmus

Hua,

Wang,

et al. 2024

Preprint

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“…RAMPAGE generates a Ramachandran plot for model assessment and distribution of residues in preferred, allowed and outer regions. The plot generated by ERRAT (https://www.doe-mbi.ucla.edu/errat/) indicates the confidence and overall quality of the model 20,21 …”

Section: Methodsmentioning

confidence: 99%

Overlapping neurological phenotypes in two extended consanguineous families with novel variants in the CNTNAP1 and ADGRG1 genes

Khan

Umair

Abbas

et al. 2023

The Journal of Gene Medicine

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BackgroundPopulation diversity is important and rare disease isolates can frequently reveal novel homozygous or biallelic mutations that lead to expanded clinical heterogeneity, with diverse clinical presentations.MethodsThe present study describes two consanguineous families with a total of seven affected individuals suffering from a clinically similar severe syndromic neurological disorder, with abnormal development and central nervous system (CNS) and peripheral nervous system (PNS) abnormalities. Whole exome sequencing (WES) and Sanger sequencing followed by 3D protein modeling was performed to identify the disease‐causing gene. RNA was extracted from the fresh blood of both families affected and healthy individuals.ResultsThe families were clinically assessed in the field in different regions of Khyber Pakhtunkhwa. Magnetic resonance imagining was obtained in the probands and blood was collected for DNA extraction and WES was performed. Sanger sequencing confirmed a homozygous, likely pathogenic mutation (GRCh38: chr17:42684199G>C; (NM_003632.3): c.333G>C);(NP_003623.1): p.(Trp111Cys) in the CNTNAP1 gene in family A, previously associated with Congenital Hypo myelinating Neuropathy 3 (CHN3; OMIM # 618186) and a novel nonsense variant in family B, (GRCh38: chr16: 57654086C>T; NC_000016.10 (NM_001370440.1): c.721C>T); (NP_001357369.1): p.(Gln241Ter) in the ADGRG1 gene previously associated with bilateral frontoparietal polymicrogyria (OMIM # 606854); both families have extended CNS and PNS clinical manifestations. In addition, 3D protein modeling was performed for the missense variant, p.(Trp111Cys), identified in the CNTNAP1, suggesting extensive secondary structure changes that might lead to improper function or downstream signaling. No RNA expression was observed in both families affected and healthy individuals hence showing that these genes are not expressed in blood.ConclusionsIn the present study, two novel biallelic variants in the CNTNAP1 and ADGRG1 genes in two different consanguineous families with a clinical overlap in the phenotype were identified. Thus, the clinical and mutation spectrum is expanded to provide further evidence that CNTNAP1 and ADGRG1 are very important for widespread neurological development.

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Case report: A novel de novo loss of function variant in the DNA-binding domain of TBX2 causes severe osteochondrodysplasia

Cited by 2 publications

References 25 publications

Frameshift variants inTBX2underlie autosomal-dominant hearing loss with incomplete penetrance of nystagmus

Frameshift variants inTBX2underlie autosomal-dominant hearing loss with incomplete penetrance of nystagmus

Overlapping neurological phenotypes in two extended consanguineous families with novel variants in the CNTNAP1 and ADGRG1 genes

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