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Am J Hum Genet. 2016 Jun 2;98(6):1235-1242. doi: 10.1016/j.ajhg.2016.03.030.

Mutations in TKT Are the Cause of a Syndrome Including Short Stature, Developmental Delay, and Congenital Heart Defects.

Author information

1
College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
2
Metabolic Unit, Department of Clinical Chemistry, Neuroscience Campus Amsterdam, VU University Medical Center Amsterdam, 1081 HV Amsterdam, the Netherlands.
3
Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
4
Division of Genetics, Boston Children's Hospital, Boston, MA 02115, USA.
5
Department of Medical Genetics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
6
GeneDx, Gaithersburg, MD 20877, USA.
7
Department of Pediatrics, Columbia University, New York, NY 10032, USA.
8
Department of Pediatrics, Columbia University, New York, NY 10032, USA; Department of Medicine, Columbia University, New York, NY 10032, USA. Electronic address: wkc15@columbia.edu.

Abstract

Whole-exome sequencing (WES) is increasingly being utilized to diagnose individuals with undiagnosed disorders. Developmental delay and short stature are common clinical indications for WES. We performed WES in three families, using proband-parent trios and two additional affected siblings. We identified a syndrome due to an autosomal-recessively inherited deficiency of transketolase, encoded by TKT, on chromosome 3p21. Our series includes three families with a total of five affected individuals, ranging in age from 4 to 25 years. Two families of Ashkenazi Jewish ancestry were homozygous for an 18 base pair in-frame insertion in TKT. The third family was compound heterozygous for nonsense and missense variants in TKT. All affected individuals had short stature and were developmentally delayed. Congenital heart defects were noted in four of the five affected individuals, and there was a history of chronic diarrhea and cataracts in the older individuals with the homozygous 18 base pair insertion. Enzymatic testing confirmed significantly reduced transketolase activity. Elevated urinary excretion of erythritol, arabitol, ribitol, and pent(ul)ose-5-phosphates was detected, as well as elevated amounts of erythritol, arabitol, and ribitol in the plasma of affected individuals. Transketolase deficiency reduces NADPH synthesis and nucleic acid synthesis and cell division and could explain the problems with growth. NADPH is also critical for maintaining cerebral glutathione, which might contribute to the neurodevelopmental delays. Transketolase deficiency is one of a growing list of inborn errors of metabolism in the non-oxidative part of the pentose phosphate pathway.

KEYWORDS:

TKT; congenital heart disease; neurodevelopmental disability; pentose phosphate pathway; transketolase deficiency

PMID:
27259054
PMCID:
PMC4908149
DOI:
10.1016/j.ajhg.2016.03.030
[Indexed for MEDLINE]
Free PMC Article

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