Identification of a novel <scp><i>TBX5</i></scp> c.755 + 1 G &gt; A variant and related pathogenesis in a family with <scp>Holt–Oram</scp> syndrome

Wang, Degang; Dong, Xingsheng; Xiong, Yi; Li, Zhiming; Xie, Yuan; Huang, Tian-Hua

doi:10.1002/ajmg.a.62488

Cited by 3 publications

(2 citation statements)

References 52 publications

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“…The whole exome sequencing (WES) was performed as previously described 11 . Brie y, genomic DNA of the proband was extracted from peripheral blood.…”

Section: Whole Exome Sequencingmentioning

confidence: 99%

Identification of compound heterozygous deletions in the WWOX gene caused WOREE syndrome by whole exome sequencing

Dong

Wen

Zhang

et al. 2023

Preprint

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Background WWOXbiallelic and loss-of-function pathogenic variants cause WWOX-related epileptic encephalopathy (WOREE syndrome), which has been reported in 60 patients to date. In this study, we report on a WOREE syndrome patient who presented with early-onset refractory seizures and global neurodevelopmental delay and died at the age of two and a half years. Methods We present clinical and molecular findings in the patient, including biallelic pathogenic variants in the WWOX gene. We employed different molecular approaches, such as whole exon sequencing, quantitative real-time polymerase chain reaction (PCR), and whole-genome sequencing, to identify the genetic defects. The breakpoints were determined through gap PCR and Sanger sequencing. Result Whole exon sequencing revealed homozygous exon 6 deletions in the WWOX gene in the proband. Quantitative real-time PCR confirmed that the deletions were inherited from each parent. However, using whole-genome sequencing, we identified three larger deletions (intron 5, exon 6, and exon 6-8) involving the WWOX gene in the proband, with deletion sizes of 13,261, 53,904, and 177,200 bp. The exact breakpoints were confirmed through gap PCR and Sanger sequencing. We found that the proband inherited the discontinuous deletion of intron 5 and exon 6 from the father, and the exons 6-8 deletion from the mother using gap PCR. Conclusion Our findings extend the variant spectrum of WOREE syndrome and support the critical role of the WWOX gene in neural development.

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“…The whole exome sequencing (WES) was performed as previously described 11 . Brie y, genomic DNA of the proband was extracted from peripheral blood.…”

Section: Whole Exome Sequencingmentioning

confidence: 99%

Identification of compound heterozygous deletions in the WWOX gene caused WOREE syndrome by whole exome sequencing

Dong

Wen

Zhang

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…The whole exome sequencing (WES) was performed as previously described [11]. Briefly, genomic DNA of the proband was extracted from peripheral blood.…”

Section: Whole Exome Sequencingmentioning

confidence: 99%

Identification of compound heterozygous deletion of the WWOX gene in WOREE syndrome

Dong,

Wen,

Zhang

et al. 2023

BMC Med Genomics

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Background Biallelic loss-of-function variants in WWOX cause WWOX-related epileptic encephalopathy (WOREE syndrome), which has been reported in 60 affected individuals to date. In this study, we report on an affected individual with WOREE syndrome who presented with early-onset refractory seizures and global neurodevelopmental delay and died at the age of two and a half years. Methods We present clinical and molecular findings in the affected individual, including biallelic pathogenic variants in the WWOX gene. We employed different molecular approaches, such as whole exome sequencing, quantitative real-time polymerase chain reaction (qPCR), and whole-genome sequencing, to identify the genetic variants. The breakpoints were determined through gap PCR and Sanger sequencing. Result Whole exome sequencing revealed homozygous exon 6 deletion in the WWOX gene in the proband. Quantitative real-time PCR confirmed that the parents were heterozygous carriers of exon 6 deletion. However, using whole-genome sequencing, we identified three larger deletions (maternal allele with exon 6–8 deletion and paternal allele with two deletions in proximity one in intron 5 and the other in exon 6) involving the WWOX gene in the proband, with deletion sizes of 13,261 bp, 53,904 bp, and 177,200 bp. The exact breakpoints were confirmed through gap PCR and Sanger sequencing. We found that the proband inherited the discontinuous deletion of intron 5 and exon 6 from the father, and the exons 6–8 deletion from the mother using gap PCR. Conclusion Our findings extend the variant spectrum of WOREE syndrome and support the critical role of the WWOX gene in neural development.

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Identification of a novel TBX5 c.755 + 1 G > A variant and related pathogenesis in a family with Holt–Oram syndrome

Wang

Dong

Xiong

et al. 2021

American J of Med Genetics Pt A

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The proband with congenital heart disease and abnormal thumb was clinically diagnosed as Holt–Oram syndrome (HOS). A novel variant, T‐box transcription factor 5 (TBX5) c.755 + 1 G > A, was identified in the proband via whole exome sequencing and validated using Sanger sequencing. Pedigree analysis and clinical examinations revealed three/seven individuals over three generations within the family, with features suggestive of HOS. Deep amplicon sequencing confirmed that the allele frequencies of the novel variant in the proband (III‐1), her brother (III‐2), and her mother (II‐2) were 50%, 48.3%, and 38.1%, respectively, indicating that III‐1 and III‐2 harbored heterozygous variants, while II‐2 harbored mosaic heterozygous variants. The minigene splicing assay showed that the novel variant affected the normal splicing of exon 7, resulting in the production of abnormal TBX5 transcripts. Reverse transcription‐quantitative polymerase chain reaction and western blot analyses revealed that the novel variant upregulated TBX5 expression at the transcriptional and translational levels. Nuclear localization assay demonstrated impaired nuclear localization of the mutant TBX5. Cell viability assay revealed the inhibition of cell activity by the mutant TBX5. Our findings indicate that the novel variant was potentially induced HOS, probably by causing aberrant splicing, reducing the enrichment of nuclear TBX5 protein, and inhibiting cellular proliferation.

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Identification of a novel TBX5 c.755 + 1 G > A variant and related pathogenesis in a family with Holt–Oram syndrome

Cited by 3 publications

References 52 publications

Identification of compound heterozygous deletions in the WWOX gene caused WOREE syndrome by whole exome sequencing

Identification of compound heterozygous deletions in the WWOX gene caused WOREE syndrome by whole exome sequencing

Identification of compound heterozygous deletion of the WWOX gene in WOREE syndrome

Identification of a novel TBX5 c.755 + 1 G > A variant and related pathogenesis in a family with Holt–Oram syndrome

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