Clinical application of massively parallel sequencing in the molecular diagnosis of glycogen storage diseases of genetically heterogeneous origin

Wang, Jing; Cui, Hong; Lee, Ni‐Chung; Hwu, Wuh‐Liang; Chien, Yin‐Hsiu; Craigen, William J.; Wong, Lee‐Jun C.; Zhang, Victor Wei

doi:10.1038/gim.2012.104

Cited by 62 publications

(63 citation statements)

References 30 publications

(29 reference statements)

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“…It has been reported that after Sanger sequencing, patients suspected of having either GSD type IV or GSD type Ia were confirmed to have GSD type III; suspicion of the former disease types probably arose because the patients had not yet developed the full spectrum of symptoms at the time of clinical assessment or presented with atypical clinical symptoms. 8,12 Massive parallel sequencing offers a complete definition of the captured gene without the need for stepwise testing and having to choose which gene to sequence first. Thus, based on the results of the present study and those of previous reports, 8,12 massive parallel sequencing should be performed to confirm what would appear to be very clear GSD types.…”

Section: Discussionmentioning

confidence: 99%

“…8,12 Massive parallel sequencing offers a complete definition of the captured gene without the need for stepwise testing and having to choose which gene to sequence first. Thus, based on the results of the present study and those of previous reports, 8,12 massive parallel sequencing should be performed to confirm what would appear to be very clear GSD types.…”

Section: Discussionmentioning

confidence: 99%

“…Massive parallel sequencing reduces the costs and turnaround time associated with the use of a single capture reagent because several samples' exons and genes can be analyzed simultaneously. 8 The capture of GSD candidate genes has been used in a validation cohort 8 and was shown to be 100% sensitive and specific. However, it has not been used for making diagnoses in a discovery cohort as described in the present work.…”

Section: Discussionmentioning

confidence: 99%

“…4 This very cost-effective technology is particularly appropriate for screening for mutations in disorders with highly heterogeneous genetic backgrounds, such as GSD, congenital disorder of glycosylation, lysosomal disorders, and mitochondrial disorders [5][6][7][8] In addition, its ability to detect mutations in large genes and to identify copy number variations is very advantageous. The implementation of massive parallel sequencing has begun to revolutionize the field of genetic diagnosis.…”

Section: Introductionmentioning

confidence: 99%

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Molecular diagnosis of glycogen storage disease and disorders with overlapping clinical symptoms by massive parallel sequencing

Vega

Medrano

Navarrete

et al. 2016

Genetics in Medicine

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Purpose: Glycogen storage disease (GSD) is an umbrella term for a group of genetic disorders that involve the abnormal metabolism of glycogen; to date, 23 types of GSD have been identified. The nonspecific clinical presentation of GSD and the lack of specific biomarkers mean that Sanger sequencing is now widely relied on for making a diagnosis. However, this gene-by-gene sequencing technique is both laborious and costly, which is a consequence of the number of genes to be sequenced and the large size of some genes. Methods:This work reports the use of massive parallel sequencing to diagnose patients at our laboratory in Spain using either a customized gene panel (targeted exome sequencing) or the Illumina Clinical-Exome TruSight One Gene Panel (clinical exome sequencing (CES)). Sequence variants were matched against biochemical and clinical hallmarks.Results: Pathogenic mutations were detected in 23 patients. Twenty-two mutations were recognized (mostly loss-of-function mutations), including 11 that were novel in GSD-associated genes. In addition, CES detected five patients with mutations in ALDOB, LIPA, NKX2-5, CPT2, or ANO5. Although these genes are not involved in GSD, they are associated with overlapping phenotypic characteristics such as hepatic, muscular, and cardiac dysfunction. Conclusions:These results show that next-generation sequencing, in combination with the detection of biochemical and clinical hallmarks, provides an accurate, high-throughput means of making genetic diagnoses of GSD and related diseases. Genet Med advance online publication 25 February 2016

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Molecular diagnosis of glycogen storage disease and disorders with overlapping clinical symptoms by massive parallel sequencing

Vega

Medrano

Navarrete

et al. 2016

Genetics in Medicine

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“…These fasting studies have merely been replaced after the introduction of new laboratory techniques, like acylcarnitine profiling (Millington et al 1990). More recently, next-generation sequencing and exome sequencing have developed into powerful diagnostic confirmatory tests (Wang et al 2012). In our experience, there are few indications for the traditional clinical fasting studies, under exceptional circumstances and well-controlled conditions, to characterize the clinical in vivo implications for patients with unknown variations in the metabolome or genome.…”

Section: Discussionmentioning

confidence: 99%

Normoglycemic Ketonemia as Biochemical Presentation in Ketotic Glycogen Storage Disease

et al. 2015

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Background: According to the textbooks, the ketotic glycogen storage disease (GSD) types 0, III, VI, IX, and XI are associated with fasting ketotic hypoglycemia and considered milder as gluconeogenesis is intact.Methods: A retrospective cohort study of biochemical profiles from supervised clinical fasting studies is performed in ketotic GSD patients in our metabolic center. For data analysis, hypoglycemia was defined as plasma glucose concentration <2.6 mmol/L. Total KB was defined as the sum of blood acetoacetate and b-hydroxybutyrate concentrations. If the product of glucose and KB concentrations was greater than 10, a ketolysis defect was suspected.Results: Data could be collected from 13 fasting studies in 12 patients with GSD III (n ¼ 4), GSD VI (n ¼ 3), and GSD IX (n ¼ 5). Six patients remained normoglycemic with median glucose concentration of 3.9 mmol/L (range, 2.8-4.6 mmol/L) and median total KB concentration of 1.9 mmol/L (range, 0.6-5

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Glycogen Storage Diseases

Cox

2017

Encyclopedia of Life Sciences

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Glycogen is a dense repository of energy which is present mostly in animal tissues; with its highly arborised structure, the glycogen dendrimer is a source of readily accessible glucose units at low osmotic cost. Access to, and accretion of glycogen is subject to fine metabolic and hormonal regulation; indeed, glycogen biosynthesis is driven by high‐energy phosphate‐bond energy, requiring also the participation of several unique protein complexes. Seminal research by Carl and Gerty Cori into the pathophysiology of glycogen metabolism opened up scientific universe of hormonal signalling, phosphorylation control and second messengers. That the glycogen storage disorder, Pompe disease, proved to be an inborn error affecting lysosome function demonstrated the crucial importance of lysosomal autophagy in cellular housekeeping. The polyglucosan body diseases, characterised by insoluble starch‐like deposits, reveal the critical role of macromolecular remodelling for the symmetrical compaction of branched glycogen structures to ensure that safe storage in the cytoplasm is combined with rapid metabolic access. Inherited defects in proteins which regulate glycogen metabolism, those which enact glycogenolysis and glycogen synthesis cause pathological glycogen accumulation – or prevent its formation. Defects in glycolysis also have consequential metabolic effects on glycogen storage. Latterly, at least eight human loci which harbour mutations associated with polyglucosan and Lafora body disease have been reported in these clinically diverse, but fatal, multisystem disorders. The principal defects identify pathways responsible for the unique control of glycogen metabolism in neurons; other conditions point to coregulation of glycogen metabolism and control of immune and inflammatory responses. Glycogen is an essential macromolecule, the adaptive advantages of which come at a cost. Disorders affecting the dynamic metabolism, regulation and maintenance of this vital energy source offer unique insights into a vast interactive network of molecular cell physiology. Key Concepts Glycogen is an essential intracellular macromolecule; its highly branched but compacted polymeric structure facilitates the rapid availability of glucose units for metabolic utilisation. With ≈55 000 linked glucose units, mature glycogen is a highly ordered sphere with a low intrinsic osmotic burden (molecular mass ≈ 10 7 Da). Glycogen is near ubiquitous in cells including neurons; but it is most abundant in muscle tissue, including cardiac muscle, and in the liver. Skeletal muscle provides the greatest net repository of glycogen for short‐lived bursts of ATP generation but the concentration in liver tissue is several‐fold greater. Liver glycogen is principally used to maintain interprandial glucose homeostasis. Appropriate molecular compaction of its symmetrical, highly branched structure maintains the solubility of glycogen in the cytoplasm – it also promotes access of metabolic enzymes, including complex protein assemblies which regulate the supply of glucose energy from its breakdown. To maintain optimal functional integrity, the branched structure of glycogen is constitutively remodelled by autophagy in the lysosomal compartment. With a short half‐life, glycogen undergoes dynamic interactions; its synthesis and degradation are subject to fine metabolic control. Inborn errors of biosynthesis and catabolism, including disorders of glycolysis, not only affect the abundance and availability of metabolic glucose released from intracellular glycogen but can also lead to altered glycogen storage and its macromolecular structure. Defects in proteins that regulate glycogen metabolism and transport, as well as those which catalyse its biosynthesis and breakdown, cause pathological – or defective – accumulation of glycogen in diverse tissues. Failure to synthesise glycogen and defective glycogenolysis lead to complex metabolic disturbances characterised by interprandial hypoglycaemia; accumulation of aberrant glycogen structures has additional pathological effects due to cellular toxicity. Glycogen storage disorders reveal much about the physiological biochemistry of glycogen and regulatory processes in the dynamic control of energy metabolism – including the special case of neuronal tissue.

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Clinical application of massively parallel sequencing in the molecular diagnosis of glycogen storage diseases of genetically heterogeneous origin

Cited by 62 publications

References 30 publications

Molecular diagnosis of glycogen storage disease and disorders with overlapping clinical symptoms by massive parallel sequencing

Molecular diagnosis of glycogen storage disease and disorders with overlapping clinical symptoms by massive parallel sequencing

Normoglycemic Ketonemia as Biochemical Presentation in Ketotic Glycogen Storage Disease

Glycogen Storage Diseases

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