Usher syndrome type 2A complicated with glycogen storage disease type 3 due to paternal uniparental isodisomy of chromosome 1 in a sporadic patient.

BACKGROUND: The condition of uniparental disomy (UPD) occurs when an individual inherits two copies of a chromosome, or part of a chromosome, from one parent. Most cases of uniparental heterodisomy (UPhD) do not cause diseases, whereas cases of uniparental isodisomy (UPiD), while rare, may be pathogenic. Theoretically, UPiD may cause rare genetic diseases in a homozygous recessive manner. METHODS: A 4-year-old girl presented with congenital hearing loss, developmental delay, hepatomegaly, and other clinical features. She and her parents were genetically tested using trio whole exome sequencing (Trio-WES) and copy number variation sequencing (CNV-seq). In addition, we built a structural model to further examine the pathogenicity of the UPiD variants. RESULTS: Trio-WES identified a paternal UPiD in chromosome 1, and two homozygous pathogenic variants AGL c.4284T>G/p.Tyr1428* and USH2A c.6528T>A/p.Tyr2176* in the UPiD region. We further analyzed the pathogenicity of these two variations. The patient was diagnosed with Usher syndrome type 2A (USH2A) and glycogen storage disease type III (GSD3). CONCLUSIONS: Our study reports a rare case of a patient carrying two pathogenic variants of different genes caused by paternal UPiD, supporting the potential application of Trio-WES in detecting and facilitating the diagnosis of UPD.

Late presentation of glycogen storage disease types Ia and III in children with short stature and hepatomegaly.

BACKGROUND: Glycogen storage diseases (GSDs) are a collection of disorders related to glycogen synthesis or degradation that classically present in infancy with hypoglycemia, failure to thrive and hepatomegaly; however, their phenotype can vary significantly. CASE PRESENTATION: We present the cases of two children, 5 years old and 3.5 years old, who were referred to endocrinology for short stature. They were ultimately found to have hepatomegaly, fasting hypoglycemia, mild elevation of transaminases and ketosis. Laboratory and genetic studies were consistent with double heterozygosity for GSDs Ia and III, with one novel mutation discovered in each patient. Nightly, both children were treated with cornstarch, which resulted in resolution of laboratory abnormalities and improvement in their growth velocity. These cases are unusual in that GSD was diagnosed relatively late in life in patients with no previous history of severe hypoglycemia. CONCLUSIONS: They highlight the importance of considering glycogen storage disease in a child presenting with short stature, as it is a treatable disease that can be diagnosed non-invasively with genetic testing.

Study of consanguineous populations can improve the annotation of SNP databases.

Our view of SNPs has evolved significantly from harmless mutational events that accumulated through the history of human race to important players in human health and disease. As a result, determining the pathologic vs. benign nature of SNPs on pure statistical basis is now viewed as too simplistic. Here, we show that two previously reported SNPs in COL6A2 and AGL represent disease-causing mutation for Ullrich Muscular Dystrophy and Glycogenosis type III, respectively, in homoallelic state. This report urges caution in interpreting SNPs in databases in the clinical genetics setting and calls for sequencing runs of homozygosity in healthy individuals as a promising approach to better annotate SNP databases.

A role for AGL ubiquitination in the glycogen storage disorders of Lafora and Cori's disease.

Cori's disease is a glycogen storage disorder characterized by a deficiency in the glycogen debranching enzyme, amylo-1,6-glucosidase,4-alpha-glucanotransferase (AGL). Here, we demonstrate that the G1448R genetic variant of AGL is unable to bind to glycogen and displays decreased stability that is rescued by proteasomal inhibition. AGL G1448R is more highly ubiquitinated than its wild-type counterpart and forms aggresomes upon proteasome impairment. Furthermore, the E3 ubiquitin ligase Malin interacts with and promotes the ubiquitination of AGL. Malin is known to be mutated in Lafora disease, an autosomal recessive disorder clinically characterized by the accumulation of polyglucosan bodies resembling poorly branched glycogen. Transfection studies in HepG2 cells demonstrate that AGL is cytoplasmic whereas Malin is predominately nuclear. However, after depletion of glycogen stores for 4 h, approximately 90% of transfected cells exhibit partial nuclear staining for AGL. Furthermore, stimulation of cells with agents that elevate cAMP increases Malin levels and Malin/AGL complex formation. Refeeding mice for 2 h after an overnight fast causes a reduction in hepatic AGL levels by 48%. Taken together, these results indicate that binding to glycogen crucially regulates the stability of AGL and, further, that its ubiquitination may play an important role in the pathophysiology of both Lafora and Cori's disease.