Dataset Information

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

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.

SUBMITTER: Boyle L

PROVIDER: S-EPMC4908149 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Boyle Lia L Wamelink Mirjam M C MMC Salomons Gajja S GS Roos Birthe B Pop Ana A Dauber Andrew A Hwa Vivian V Andrew Melissa M Douglas Jessica J Feingold Murray M Kramer Nancy N Saitta Sulagna S Retterer Kyle K Cho Megan T MT Begtrup Amber A Monaghan Kristin G KG Wynn Julia J Chung Wendy K WK

American journal of human genetics 20160601 6

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 ...[more]

PMID: 27259054

Similar Datasets

Project description:BackgroundKrüppel-type zinc finger genes (ZNF) constitute a large yet relatively poorly characterized gene family. ZNF genes encode proteins that recognize specific DNA motifs in gene promotors. They act as transcriptional co-activators or -repressors via interaction with chromatin remodeling proteins and other transcription factors. Only few ZNF genes are currently linked to human disorders and identification of ZNF gene-associated human diseases may help understand their function. Here we provide genetic, statistical, and clinical evidence to support association of ZNF148 with a new intellectual disability (ID) syndrome disorder.MethodsRoutine diagnostic exome sequencing data were obtained from 2172 patients with ID and/or multiple congenital anomalies.ResultsIn a cohort of 2172 patient-parent trios referred for routine diagnostic whole exome sequencing for ID and/or multiple congenital anomalies (MCA) in the period 2012-2016, four patients were identified who carried de novo heterozygous nonsense or frameshift mutations in the ZNF148 gene. This was the only ZNF gene with recurrent truncating de novo mutations in this cohort. All mutations resulted in premature termination codons in the last exon of ZNF148. The number of the de novo truncating mutations in the ZNF148 gene was significantly enriched (p = 5.42 × 10-3). The newly described ZNF148-associated syndrome is characterized by underdevelopment of the corpus callosum, mild to moderate developmental delay and ID, variable microcephaly or mild macrocephaly, short stature, feeding problems, facial dysmorphisms, and cardiac and renal malformations.ConclusionsWe propose ZNF148 as a gene involved in a newly described ID syndrome with a recurrent phenotype and postulate that the ZNF148 is a hitherto unrecognized but crucial transcription factor in the development of the corpus callosum. Our study illustrates the advantage of whole exome sequencing in a large cohort using a parent-offspring trio approach for identifying novel genes involved in rare human diseases.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets