Whole Exome Sequencing detects PYGM variants in two adults with McArdle disease

McArdle disease is a progressive and debilitating glycogen storage disease with typical onset in late childhood. Here we describe a former competitive athlete with early adult onset McArdle disease and a septuagenarian with a history of exercise-intolerance since adolescence who was evaluated for proximal muscle weakness. Exome sequencing identified bi-allelic variants in PYGM gene for both cases. The former athlete has the common, well-known pathogenic variant p.(Arg50Ter) in trans with a novel missense variant, p.(Asp694Glu). The second individual has a previously described homozygous missense variant, p.(Arg771Gln). Here, we describe the clinical course, enzyme-testing results using muscle tissue and molecular findings for the individuals, and add to the knowledge of the genotypic spectrum of this disorder.

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Whole exome sequencing in foetal akinesia expands the genotype–phenotype spectrum of GBE1 glycogen storage disease mutations

Neuromuscular Disorders ◽

10.1016/j.nmd.2012.11.005 ◽

2013 ◽

Vol 23 (2) ◽

pp. 165-169 ◽

Cited By ~ 21

Author(s):

Gianina Ravenscroft ◽

Elizabeth M. Thompson ◽

Emily J. Todd ◽

Kyle S. Yau ◽

Nina Kresoje ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Glycogen Storage Disease ◽

Storage Disease ◽

Glycogen Storage ◽

Disease Mutations ◽

Whole Exome

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A founder AGL mutation causing glycogen storage disease type IIIa in Inuit identified through whole-exome sequencing: a case series

Canadian Medical Association Journal ◽

10.1503/cmaj.140840 ◽

2015 ◽

Vol 187 (2) ◽

pp. E68-E73 ◽

Cited By ~ 8

Author(s):

Isabelle Rousseau-Nepton ◽

Minoru Okubo ◽

Rosemarie Grabs ◽

John Mitchell ◽

Constantin Polychronakos ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Glycogen Storage Disease ◽

Storage Disease ◽

Case Series ◽

Glycogen Storage Disease Type ◽

Glycogen Storage ◽

Disease Type ◽

Type Iiia ◽

Whole Exome

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Application of whole exome sequencing to a rare inherited metabolic disease with neurological and gastrointestinal manifestations: A congenital disorder of glycosylation mimicking glycogen storage disease

Clinica Chimica Acta ◽

10.1016/j.cca.2015.02.008 ◽

2015 ◽

Vol 444 ◽

pp. 50-53 ◽

Cited By ~ 7

Author(s):

Rihwa Choi ◽

Hye In Woo ◽

Byung-Ho Choe ◽

Seungman Park ◽

Yeomin Yoon ◽

...

Keyword(s):

Metabolic Disease ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Glycogen Storage Disease ◽

Storage Disease ◽

Glycogen Storage ◽

Gastrointestinal Manifestations ◽

Inherited Metabolic Disease ◽

Congenital Disorder Of Glycosylation ◽

Whole Exome

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Neurological Involvement in Glycogen Storage Disease Type IXa due to PHKA2 Mutation

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/cjn.2020.18 ◽

2020 ◽

Vol 47 (3) ◽

pp. 400-403 ◽

Cited By ~ 1

Author(s):

Chelsea Smith ◽

Marie-Josée Dicaire ◽

Bernard Brais ◽

Roberta La Piana ◽

Keyword(s):

Storage Disease ◽

Glycogen Synthesis ◽

Missense Variant ◽

Glycogen Storage Disease Type ◽

Glycogen Storage ◽

Regulatory Subunit ◽

Neurological Involvement ◽

Phosphorylase Kinase ◽

Glycogen Storage Diseases ◽

Whole Exome

ABSTRACT:Glycogen storage diseases (GSDs) result from the deficiency of enzymes involved in glycogen synthesis and breakdown into glucose. Mutations in the gene PHKA2 encoding phosphorylase kinase regulatory subunit alpha 2 have been linked to GSD type IXa. We describe a family with two adult brothers with neonatal hepatosplenomegaly and later onset of hearing loss, cognitive impairment, and cerebellar involvement. Whole-exome sequencing was performed on both subjects and revealed a shared hemizygous missense variant (c.A1561G; p.T521A) in exon 15 of PHKA2. The phenotype broadens the clinical and magnetic resonance imaging spectrum of GSD type IXa to include later onset neurological manifestations.

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The natural history of glycogen storage disease types VI and IX: Long-term outcome from the largest metabolic center in Canada

Molecular Genetics and Metabolism ◽

10.1016/j.ymgme.2014.09.005 ◽

2014 ◽

Vol 113 (3) ◽

pp. 171-176 ◽

Cited By ~ 43

Author(s):

Anne Roscher ◽

Jaina Patel ◽

Stacy Hewson ◽

Laura Nagy ◽

Annette Feigenbaum ◽

...

Keyword(s):

Natural History ◽

Glycogen Storage Disease ◽

Storage Disease ◽

Glycogen Storage ◽

Term Outcome ◽

Long Term Outcome ◽

History Of

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Whole exome sequencing identifies FOXL2, FOXA2 and FOXA3 as candidate genes for monogenic congenital anomalies of the kidneys and urinary tract

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab253 ◽

2021 ◽

Author(s):

Bixia Zheng ◽

Steve Seltzsam ◽

Chunyan Wang ◽

Luca Schierbaum ◽

Sophia Schneider ◽

...

Keyword(s):

Urinary Tract ◽

Exome Sequencing ◽

Candidate Genes ◽

Whole Exome Sequencing ◽

Congenital Anomalies ◽

De Novo ◽

Horseshoe Kidney ◽

Missense Variant ◽

Whole Exome ◽

Fox Genes

Abstract Background Congenital anomalies of the kidneys and urinary tract (CAKUT) constitute the most common cause of chronic kidney disease in the first three decades of life. Variants in four Forkhead box (FOX) transcription factors have been associated with CAKUT. We hypothesized that other FOX genes, if highly expressed in developing kidney, may also represent monogenic causes of CAKUT. Methods We here performed whole exome sequencing (WES) in 541 families with CAKUT and generated 4 lists of CAKUT candidate genes: A) 36 FOX genes showing high expression during renal development, B) 4 FOX genes known to cause CAKUT to validate list A; C) 80 genes that we identified as unique potential novel CAKUT candidate genes when performing WES in 541 CAKUT families, and D) 175 genes identified from WES as multiple potential novel CAKUT candidate genes. Results To prioritize potential novel CAKUT candidates in FOX gene family, we overlapped 36 FOX genes (list A) with list C and D of WES-derived CAKUT candidates. Intersection with list C, identified a de novo FOXL2 in-frame deletion in a patient with eyelid abnormalities and ureteropelvic junction obstruction, and a homozygous FOXA2 missense variant in a patient with horseshoe kidney. Intersection with list D, identified a heterozygous FOXA3 missense variant in a CAKUT family with multiple affected individuals. Conclusion We hereby identified FOXL2, FOXA2 and FOXA3 as novel monogenic candidate genes of CAKUT, supporting the utility of a paralog-based approach to discover mutated genes associated with human disease.

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A homozygous mutation of GNRHR in a familial case diagnosed with polycystic ovary syndrome

Acta Endocrinologica ◽

10.1530/eje-16-0968 ◽

2017 ◽

Vol 176 (5) ◽

pp. K9-K14 ◽

Cited By ~ 5

Author(s):

Sandrine Caburet ◽

Ronit Beck Fruchter ◽

Bérangère Legois ◽

Marc Fellous ◽

Stavit Shalev ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Sanger Sequencing ◽

Polycystic Ovary ◽

Missense Variant ◽

Genetic Alterations ◽

Homozygous Mutation ◽

Gonadotropin Secretion ◽

Whole Exome ◽

A Genome

Context PCOS is a heterogeneous condition characterized by hyperandrogenism and chronic anovulation and affects about 10% of women. Its etiology is poorly known, but a dysregulation of gonadotropin secretion is one of its hallmarks. Objective As the etiology of PCOS is unclear, we have performed a genome-wide analysis of a consanguineous family with three sisters diagnosed with PCOS. Methods Whole-exome sequencing and Sanger sequencing confirmation. Results Whole-exome sequencing allowed the detection of the missense variant rs104893836 located in the first coding exon of the GNRHR gene and leading to the p.Gln106Arg (p.Q106R) substitution. Sanger sequencing of all available individuals of the family confirmed that the variant was homozygous in the three affected sisters and heterozygous in both parents. Conclusions This is the first description of a GNRHR gene mutation in patients diagnosed with PCOS. Although we do not exclude a possible interaction of the identified variant with the genetic background and/or the environment, our result suggests that genetic alterations in the hypothalamo–pituitary axis may play role in the pathogenesis of PCOS.

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The Use of Whole Genome and Exome Sequencing for Newborn Screening: Challenges and Opportunities for Population Health

Frontiers in Pediatrics ◽

10.3389/fped.2021.663752 ◽

2021 ◽

Vol 9 ◽

Author(s):

Audrey C. Woerner ◽

Renata C. Gallagher ◽

Jerry Vockley ◽

Aashish N. Adhikari

Keyword(s):

Newborn Screening ◽

Exome Sequencing ◽

Genetic Disorders ◽

Population Based ◽

Lessons Learned ◽

Screening Tests ◽

Whole Genome ◽

Whole Exome ◽

Challenges And Opportunities ◽

History Of

Newborn screening (NBS) is a population-based program with a goal of reducing the burden of disease for conditions with significant clinical impact on neonates. Screening tests were originally developed and implemented one at a time, but newer methods have allowed the use of multiplex technologies to expand additions more rapidly to standard panels. Recent improvements in next-generation sequencing are also evolving rapidly from first focusing on individual genes, then panels, and finally all genes as encompassed by whole exome and genome sequencing. The intersection of these two technologies brings the revolutionary possibility of identifying all genetic disorders in newborns, allowing implementation of therapies at the optimum time regardless of symptoms. This article reviews the history of newborn screening and early studies examining the use of whole genome and exome sequencing as a screening tool. Lessons learned from these studies are discussed, along with technical, ethical, and societal challenges to broad implementation.

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Genes and exercise intolerance: insights from McArdle disease

Physiological Genomics ◽

10.1152/physiolgenomics.00076.2015 ◽

2016 ◽

Vol 48 (2) ◽

pp. 93-100 ◽

Cited By ~ 8

Author(s):

Gisela Nogales-Gadea ◽

Richard Godfrey ◽

Alfredo Santalla ◽

Jaume Coll-Cantí ◽

Guillem Pintos-Morell ◽

...

Keyword(s):

Glycogen Storage Disease Type ◽

Tissue Level ◽

Glycogen Storage ◽

Clinical Severity ◽

Exercise Intolerance ◽

Moderate Intensity ◽

Future Research ◽

Moderate Intensity Exercise ◽

Carbohydrate Ingestion ◽

Mcardle Disease

McArdle disease (glycogen storage disease type V) is caused by inherited deficiency of a key enzyme in muscle metabolism, the skeletal muscle-specific isoform of glycogen phosphorylase, “myophosphorylase,” which is encoded by the PYGM gene. Here we review the main pathophysiological, genotypic, and phenotypic features of McArdle disease and their interactions. To date, moderate-intensity exercise (together with pre-exercise carbohydrate ingestion) is the only treatment option that has proven useful for these patients. Furthermore, regular physical activity attenuates the clinical severity of McArdle disease. This is quite remarkable for a monogenic disorder that consistently leads to the same metabolic defect at the muscle tissue level, that is, complete inability to use muscle glycogen stores. Further knowledge of this disorder would help patients and enhance understanding of exercise metabolism as well as exercise genomics. Indeed, McArdle disease is a paradigm of human exercise intolerance and PYGM genotyping should be included in the genetic analyses that might be applied in the coming personalized exercise medicine as well as in future research on genetics and exercise-related phenotypes.

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