Uniparental isodisomy of chromosome 1 results in glycogen storage disease type III with profound growth retardation

Abstract

Background Glycogen storage disease type III (GSDIII) is caused by mutations of AGL gene with debranching enzyme deficiency. Patients with GSDIII manifest fasting hypoglycemia, hepatomegaly, hepatopathy, myopathy, and cardiomyopathy. We report on an 18‐year‐old boy with a profound growth retardation (<3 SD ) besides typical clinical features of GSDIII, whereby endocrinological studies were negative. Methods and Results Molecular analysis of AGL gene revealed the homozygous reported variant c.3903_3904insA. Since discordant results from segregation studies showed the carrier status in one parent only, SNP array and short tandem repeats analyses were performed, revealing a paternal disomy of chromosome 1 (UPD1). Conclusion This study describes the first case of GSDIII resulting from UPD1. UPD can play an important role even in case of imprinted genes. DIRAS3 is a maternally imprinted tumor suppressor gene, located on chromosome 1p31, and implicated in growth and oncogenesis. It can be speculated that DIRAS3 overexpression might have a role in the severe short stature of our patient. The study emphasizes the importance of parental segregation analysis especially in patients with recessive conditions to look for specific genetic causes of disease and to estimate properly the risk of family recurrence.

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

“…Moreover, analysis of the homozygous variations in all of the genes in the loss of heterozygosity region (Table 3) showed that only the AGL and USH2A variations are pathogenic. The maternal imprinting gene DIRAS3 located on chromosome 1 may cause growth retardation (Fuke et al, 2013;Lu et al, 2016;Ponzi et al, 2019); however, the growth of our patient was normal for her age, and no variation in the gene was detected although the loss of heterozygosity region included DIRAS3.…”

“…The first case of GSD3 caused by UPD was reported recently for a patient with serious liver lesions and dysfunction, and developmental retardation (Ponzi et al, 2019 ). Similar to this case, our patient manifested typical characteristics of glycogen accumulation, such as liver enlargement and stunted growth.…”

Case Report: Genetic and Clinical Features of Maternal Uniparental Isodisomy-Induced Thiamine-Responsive Megaloblastic Anemia Syndrome

“…In patients with Zellweger syndrome, the primarily involved gene is PEX1, and the patients mainly present hypotonia, hepatic enlargement, abnormal facial bone development, epilepsy, and craniofacial abnormalities ( 19 ). Patriarchal sex single diploid involving A III genes results in glycogen III glycogen storage disease and severe dysplasia ( 20 ). The case reported here, induced by UPD in ROH (1p36.33q44), developed none of the clinical manifestations described above.…”

Hypoglycaemia Metabolic Gene Panel Testing

“…In cases of negative or partial NGS results of targeted gene panels and clinical exome sequencing, but strong evidence of biochemical or clinical phenotype or discrepancy with segregation studies, other techniques should be used, including multiple ligation-dependent probe amplification (MLPA) and high-resolution comparative genomic hybridization (CGH) array ( 1 ) ( Figure 2 ). In a recent case of GSD type III, the use of single nucleotide polymorphism (SNP) array and short tandem repeats (STR) segregation study revealed for the first time a paternal isodisomy of chromosome 1 ( 115 ). Conversely, NGS approach can help to make a diagnosis in case of negative biochemical results as in some GSDs, or in HMGCS2 mutations in which the characteristic biomarker is not always present ( 96 – 98 ).…”