Mutations in TKT Are the Cause of a Syndrome Including Short Stature, Developmental Delay, and Congenital Heart Defects.
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.
College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Lia
L
Boyle
Metabolic Unit, Department of Clinical Chemistry, Neuroscience Campus Amsterdam, VU University Medical Center Amsterdam, 1081 HV Amsterdam, the Netherlands.
Mirjam M C
MMC
Wamelink
Metabolic Unit, Department of Clinical Chemistry, Neuroscience Campus Amsterdam, VU University Medical Center Amsterdam, 1081 HV Amsterdam, the Netherlands.
Gajja S
GS
Salomons
Metabolic Unit, Department of Clinical Chemistry, Neuroscience Campus Amsterdam, VU University Medical Center Amsterdam, 1081 HV Amsterdam, the Netherlands.
Birthe
B
Roos
Metabolic Unit, Department of Clinical Chemistry, Neuroscience Campus Amsterdam, VU University Medical Center Amsterdam, 1081 HV Amsterdam, the Netherlands.
Ana
A
Pop
Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Andrew
A
Dauber
Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Vivian
V
Hwa
Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Melissa
M
Andrew
Division of Genetics, Boston Children's Hospital, Boston, MA 02115, USA.
Jessica
J
Douglas
Division of Genetics, Boston Children's Hospital, Boston, MA 02115, USA.
Murray
M
Feingold
Department of Medical Genetics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Nancy
N
Kramer
Department of Medical Genetics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Sulagna
S
Saitta
GeneDx, Gaithersburg, MD 20877, USA.
Kyle
K
Retterer
GeneDx, Gaithersburg, MD 20877, USA.
Megan T
MT
Cho
GeneDx, Gaithersburg, MD 20877, USA.
Amber
A
Begtrup
GeneDx, Gaithersburg, MD 20877, USA.
Kristin G
KG
Monaghan
Department of Pediatrics, Columbia University, New York, NY 10032, USA.
Julia
J
Wynn
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.
Wendy K
WK
Chung
D000328:Adult; D002648:Child; D002675:Child, Preschool; D002658:Developmental Disabilities / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D004392:Dwarfism / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006330:Heart Defects, Congenital / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D009249:NADP / Q000378:metabolism; D010375:Pedigree; D013577:Syndrome; D014174:Transketolase / Q000235:genetics*; D055815:Young Adult
D009249:NADP; D014174:Transketolase; D005978:Glutathione
TKT; congenital heart disease; neurodevelopmental disability; pentose phosphate pathway; transketolase deficiency