Abstract
We evaluated a family with a 16-month-old boy with cirrhosis and hepatocellular carcinoma and his 30-month-old brother with cirrhosis. After failing to identify a diagnosis after routine metabolic evaluation, we utilized a combination of RNA-Seq and whole exome sequencing to identify a novel homozygous p.Ser171Phe Transaldolase (TALDO1) variant in the proband, his brother with cirrhosis, as well as a clinically asymptomatic older 8-year-old brother. Metabolite analysis and enzymatic testing of TALDO1 demonstrated elevated ribitol, sedoheptitol, and sedoheptulose-7P, and lack of activity of TALDO1 in the three children homozygous for the p.Ser171Phe mutation. Our findings expand the phenotype of transaldolase deficiency to include early onset hepatocellular carcinoma in humans and demonstrate that, even within the same family, individuals with the same homozygous mutation demonstrate a wide range of phenotypes.
Competing interests: None declared
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Birthe Roos and Erwin Jansen are kindly acknowledged for their analytical contributions.
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Communicated by: K. Michael Gibson
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One-Sentence Summary
We utilized a combination of RNA-Seq and whole exome sequencing to identify a novel homozygous p.Ser171Phe Transaldolase (TALDO1) mutation in a 16-month-old child to develop cirrhosis and hepatocellular carcinoma and biochemically confirmed that three affected siblings demonstrate a wide range of phenotypes from being asymptomatic to cirrhosis to hepatocellular carcinoma.
Conflict of Interest
Charles A. LeDuc, Elizabeth E. Crouch, Ashley Wilson, Jay Lefkowitch, Mirjam M.C. Wamelink, Cornelis Jakobs, Gajja S Salomons, Xiaoyun Sun, Yufeng Shen, and Wendy K. Chung declare that they have no conflict of interest.
Informed Consent
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients for being included in the study.
Details of the Contributions of Individual Authors
CAL and WKC wrote the manuscript with assistance from EEC, YS, MW, CJ, and GS. JL did the histological analysis. MW, CJ, and GS did the metabolic analysis. YS and XS did the alignment and variant calling. CAL and EEC tested and analyzed the variants. AW and WKC did the clinical workup on the patient. The study was designed by WKC.
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LeDuc, C.A. et al. (2013). Novel Association of Early Onset Hepatocellular Carcinoma with Transaldolase Deficiency. In: Zschocke, J., Gibson, K., Brown, G., Morava, E., Peters, V. (eds) JIMD Reports - Volume 12. JIMD Reports, vol 12. Springer, Cham. https://doi.org/10.1007/8904_2013_254
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DOI: https://doi.org/10.1007/8904_2013_254
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